Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein

ABSTRACT

The present invention relates to processes for preparing the compounds of general formula I, 
                         
wherein the groups R 1  and R 3  are defined according to claim  1 . Furthermore this inventions relates to intermediates obtained in these processes.

This application is a Divisional of U.S. application Ser. No.12/789,859, filed May 28, 2010, which is a Divisional of U.S.application Ser. No. 11/416,683, filed May 3, 2006, which claimspriority to EP 05 010 115, filed May 10, 2005; EP 05 018 265, filed Aug.23, 2005; and EP 05 108 484, filed Sep. 15, 2005, the contents of whichare incorporated herein in their entireties.

The present invention relates to a process for preparing ofglucopyranosyl-substituted benzyl-benzene derivatives of the formula I,

wherein the substituents R¹ and R³ are defined as hereinafter.Furthermore the present invention relates to processes for preparingintermediates and starting materials of the process for preparing ofglucopyranosyl-substituted benzyl-benzene derivatives. In addition thepresent invention relates to such intermediates and starting material.

BACKGROUND OF THE INVENTION

In the international patent application WO 2005/092877glucopyranosyl-substituted benzene derivatives of the general formula

wherein the groups R¹ to R⁶ and R^(7a), R^(7b), R^(7c) are as definedtherein, are described. Such compounds have a valuable inhibitory effecton the sodium-dependent glucose cotransporter SGLT, particularly SGLT2.

AIM OF THE INVENTION

The aim of the present invention is to find new processes for preparingof glucopyranosyl-substituted benzyl-benzene derivatives of the formulaI; in particular processes with which the product may be obtained inhigh yields, high enantiomeric or diastereomeric purity and which allowthe manufacture of the product in a commercial scale with a lowtechnical expenditure and a high space/time yield.

Another aim of the present invention is to provide processes forpreparing the starting materials of the beforementioned method ofmanufacture.

Further aims of the present invention relate to new intermediates andstarting materials in the process according to the present invention.

Other aims of the present invention will become apparent to the skilledartisan directly from the foregoing and following description.

OBJECT OF THE INVENTION

In a first aspect the present invention relates to a process forpreparing the compounds of general formula I,

wherein

-   R¹ denotes cyclobutyl, cyclopentyl, cyclohexyl,    R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or    tetrahydropyran-4-yl; and-   R³ denotes hydrogen;-   characterised in that in a compound of general formula II

wherein R¹ is defined as hereinbefore and

-   R² independently of one another denote hydrogen,    (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl,    aryl-(C₁₋₃-alkyl)-carbonyl, aryl-C₁₋₃-alkyl, allyl,    R^(a)R^(b)R^(c)Si, CR^(a)R^(b)OR^(c), wherein two adjacent groups R²    may be linked with each other to form a bridging group SiR^(a)R^(b),    CR^(a)R^(b) or CR^(a)OR^(b)—CR^(a)OR^(b); with the proviso that at    least one substituent R² is not hydrogen;-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, while the alkyl may be mono- or    polysubstituted by halogen;-   L1 independently of one another are selected from among fluorine,    chlorine, bromine, C₁₋₃-alkyl, C₁₋₄-alkoxy and nitro;-   while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups, which may be mono- or polysubstituted with L1;-   the protective groups R² not being hydrogen are cleaved, in    particular hydrolysed.

In a second aspect the present invention relates to a process forpreparing the compounds of general formula II,

wherein

-   R¹ denotes cyclobutyl, cyclopentyl, cyclohexyl,    R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or    tetrahydropyran-4-yl; and-   R² independently of one another denote hydrogen,    (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl,    aryl-(C₁₋₃-alkyl)-carbonyl, aryl-C₁₋₃-alkyl, allyl,    R^(a)R^(b)R^(c)Si, CR^(a)R^(b)OR^(c), wherein two adjacent groups R²    may be linked with each other to form a bridging group SiR^(a)R^(b),    CR^(a)R^(b) or CR^(a)OR^(b)—CR^(a)OR^(b);-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, while the alkyl groups may be mono- or    polysubstituted by halogen;-   L1 independently of one another are selected from among fluorine,    chlorine, bromine, C₁₋₃-alkyl, C₁₋₄-alkoxy and nitro;-   while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups, which may be mono- or polysubstituted with L1;-   characterised in that a compound of general formula III

wherein R¹ and each R² are defined as hereinbefore and

-   R′ denotes hydrogen, C₁₋₆-alkyl, (C₁₋₄-alkyl)carbonyl,    (C₁₋₄-alkyl)oxycarbonyl, arylcarbonyl, aryl-(C₁₋₃-alkyl)-carbonyl;-   while the term “aryl” is defined as hereinbefore;-   is reacted with a reducing agent.

In a third aspect the present invention relates to a process forpreparing the compounds of general formula III,

wherein

-   R¹ denotes cyclobutyl, cyclopentyl, cyclohexyl,    R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or    tetrahydropyran-4-yl; and-   R² independently of one another denote hydrogen,    (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl,    aryl-(C₁₋₃-alkyl)-carbonyl, aryl-C₁₋₃-alkyl, allyl,    R^(a)R^(b)R^(c)Si, CR^(a)R^(b)OR^(c), wherein two adjacent groups R²    may be linked with each other to form a bridging group SiR^(a)R^(b),    CR^(a)R^(b) or CR^(a)OR^(b)—CR^(a)OR^(b); and-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, while the alkyl groups may be mono- or    polysubstituted by halogen;-   L1 independently of one another are selected from among fluorine,    chlorine, bromine, C₁₋₃-alkyl, C₁₋₄-alkoxy and nitro;-   R′ denotes hydrogen, C₁₋₆-alkyl, (C₁₋₄-alkyl)carbonyl,    (C₁₋₄-alkyl)oxycarbonyl, arylcarbonyl, aryl-(C₁₋₃-alkyl)-carbonyl;-   while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups, which may be mono- or polysubstituted with L1;-   characterised in that an organometallic compound of the formula VI

wherein R¹ is defined as hereinbefore and M denotes Li or MgHal, whereinHal denotes Cl, Br or I;

-   or a derivative thereof obtained by transmetallation;-   which compound of the formula VI may be obtained by halogen-metal    exchange or by the insertion of a metal in the carbon-halogen bond    of a halogen-benzylbenzene compound of general formula V

wherein R¹ is defined as hereinbefore and X denotes Br or I;

-   and optionally subsequent transmetallation, is added to a    gluconolactone of general formula IV

wherein R² is as hereinbefore defined,

-   then the adduct obtained is reacted with water or an alcohol R′—OH,    where R′ denotes C₁₋₆-alkyl, in the presence of an acid and    optionally the product obtained in the reaction with water wherein    R′ denotes H is converted in a subsequent reaction with an acylating    agent into the product of formula III wherein R′ denotes    (C₁₋₄-alkyl)carbonyl, (C₁₋₄-alkyl)oxycarbonyl, arylcarbonyl or    aryl-(C₁₋₃-alkyl)-carbonyl, wherein the term “aryl” is defined as    hereinbefore.

In a fourth aspect the present invention relates to a process forpreparing the compounds of general formula XXXIII,

wherein R¹, R² are defined as hereinbefore and hereinafter;

-   characterised in that a protected D-glucal of the formula XXX

wherein R² is defined as hereinbefore;

-   is metallated to yield a metallated D-glucal of the formula XXXI

wherein R² is defined as hereinbefore and M denotes lithium or amagnesium moiety;

-   which is optionally transmetallated to yield a metallated D-glucal    of the formula XXXI, wherein M denotes a magnesium, zinc, indium,    boron, tin, silicon or chromium moiety; and-   the metallated or trans-metallated D-glucal of the formula XXXI is    reacted with an aglycon of the formula V

wherein R¹ is defined as hereinbefore and X denotes a leaving group;

-   in the presence of a transition metal catalyst-   to yield a glucal derivative of the formula XXXII

wherein R¹ and R² are defined as hereinbefore; and

-   the glucal derivative of the formula XXXII is converted to the    product of the formula XXXIII by the addition of water to the double    bond of the glucal moiety, in particular by hydroboration of the    double bond and subsequent cleavage of the carbon-boron bond or by    epoxidation or dihydroxylation of the double bond and subsequent    reduction of the resultant anomeric carbon-oxygen bond.

In a fifth aspect the present invention relates to a process forpreparing the compounds of general formula XXXIII,

wherein R¹, R² are defined as hereinbefore and hereinafter;

-   characterised in that a protected D-glucal of the formula XXX

wherein R² is defined as hereinbefore;

-   is epoxidated to yield the corresponding glucaloxide of the formula    XXXIV

wherein R² is defined as hereinbefore; and

-   the glucaloxide of the formula XXXIV is reacted with a metallated    aglycon of the formula VI

wherein R¹ is defined as hereinbefore and M denotes a lithium,magnesium, zinc, indium, aluminum or boron moiety;

-   to yield the product of the formula XXXIII.

In a sixth aspect the present invention relates to a process forpreparing the compounds of general formula II,

wherein R¹, R² are defined as hereinbefore and hereinafter;

-   characterised in that a glucose derivative of the formula XXXV

wherein R² is defined as hereinbefore and

-   Hal denotes F, Cl, Br, C₁₋₃-alkylcarbonyloxy,    C₁₋₃-alkyloxycarbonyloxy or C₁₋₃-alkyloxy;-   is reacted with a metallated aglycon of the formula VI

wherein R¹ is defined as hereinbefore and M denotes a lithium,magnesium, zinc, indium or boron moiety;

-   to yield the product of the formula II.

In a seventh aspect the present invention relates to a process forpreparing the compounds of general formula V,

wherein

-   R¹ denotes cyclobutyl, cyclopentyl, cyclohexyl,    R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or    tetrahydropyran-4-yl; and-   X denotes a bromine atom or an iodine atom;-   characterised in that a benzoyl chloride derivative of the formula    XII

wherein X is defined as above; or a derivative thereof such as a benzoylanhydride, an ester or a benzonitrile;

-   is reacted with a halobenzene of the formula XXVII

wherein Z⁵ denotes a fluorine, chlorine or iodine atom;

-   in the presence of a catalyst to obtain an intermediate compound of    the formula XXVI

wherein X and Z⁵ are defined as hereinbefore; and

-   the intermediate compound of the formula XXVI is reacted with R¹—OH,    wherein R¹ is defined as hereinbefore, or an anion thereof,    preferably in a solvent or mixture of solvents, in the presence of a    base to yield a benzophenone derivative of the formula VII

wherein X and R¹ are defined as hereinbefore; and

-   the benzophenone derivative of the formula VII is reacted with a    reducing agent, preferably in a solvent or mixture of solvents, in    the presence of a Lewis acid to furnish the compound of the formula    V as defined above.

In an eighth aspect the present invention relates to a process forpreparing the compounds of general formula II,

wherein R¹ and R² are defined as hereinbefore,

-   characterized in that an aglycon of the formula V

wherein X and R¹ are defined as hereinbefore, is obtained by a processaccording to the seventh aspect of this invention, and

-   said halogen-benzylbenzene compound of general formula V is    transformed into an organometallic compound of the formula VI

wherein R¹ is defined as hereinbefore and M denotes Li or MgHal, whereinHal denotes Cl, Br or I;

-   by an halogen-metal exchange or by the insertion of a metal in the    carbon-halogen bond of the halogen-benzylbenzene compound of general    formula V, and optionally subsequent transmetallation; and-   said organometallic compound of the formula VI is reacted with a    gluconolactone of general formula IV

wherein R² is as hereinbefore defined, in accordance with the process ofthe third aspect of this invention to obtain an intermediate of theformula III,

wherein R², R′ and R¹ are defined as hereinbefore, and

-   said intermediate of the formula III is reacted with a reducing    agent in accordance with the second aspect of this invention to    obtain the compound of the formula II.

In a ninth aspect the present invention relates to compounds of generalformula II

wherein

-   R¹ denotes cyclobutyl, cyclopentyl, cyclohexyl,    R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or    tetrahydropyran-4-yl; and-   R² independently of one another denote hydrogen,    (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl,    aryl-(C₁₋₃-alkyl)-carbonyl, aryl-C₁₋₃-alkyl, allyl,    R^(a)R^(b)R^(c)Si, CR^(a)R^(b)OR^(c), wherein two adjacent groups R²    may be linked with each other to form a bridging group SiR^(a)R^(b),    CR^(a)R^(b) or CR^(a)OR^(b)—CR^(a)OR^(b); with the proviso that at    least one substituent R² does not denote hydrogen;-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, while the alkyl groups may be mono- or    polysubstituted by halogen;-   L1 independently of one another are selected from among fluorine,    chlorine, bromine, C₁₋₃-alkyl, C₁₋₄-alkoxy and nitro;-   while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups, which may be mono- or polysubstituted with L1.

In a further aspect the present invention relates to compounds ofgeneral formula III

wherein

-   R¹ denotes cyclobutyl, cyclopentyl, cyclohexyl,    R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or    tetrahydropyran-4-yl; and-   R² independently of one another denote hydrogen,    (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl,    aryl-(C₁₋₃-alkyl)-carbonyl, aryl-C₁₋₃-alkyl, allyl,    R^(a)R^(b)R^(c)Si, CR^(a)R^(b)OR^(c), wherein two adjacent groups R²    may be linked with each other to form a bridging group SiR^(a)R^(b),    CR^(a)R^(b) or CR^(a)OR^(b)—CR^(a)OR^(b);-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, while the alkyl or aryl groups may be mono-    or polysubstituted by halogen;-   L1 independently of one another are selected from among fluorine,    chlorine, bromine, C₁₋₃-alkyl, C₁₋₄-alkoxy and nitro;-   R′ denotes hydrogen, C₁₋₆-alkyl, (C₁₋₄-alkyl)carbonyl,    (C₁₋₄-alkyl)oxycarbonyl, arylcarbonyl, aryl-(C₁₋₃-alkyl)-carbonyl;-   while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups, which may be mono- or polysubstituted with L1.

In a further aspect the present invention relates to compounds ofgeneral formula VI

wherein

-   R¹ denotes cyclobutyl, cyclopentyl, cyclohexyl,    R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or    tetrahydropyran-4-yl; and-   M denotes Li or MgHal, wherein Hal denotes Cl, Br or I.

In a further aspect the present invention relates to compounds ofgeneral formula V

wherein

-   R¹ denotes cyclobutyl, cyclopentyl, cyclohexyl,    R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or    tetrahydropyran-4-yl; and-   X denotes Br or I.

In a further aspect the present invention relates to compounds of theformula VII

or of the formula XIX

wherein

-   R¹ denotes cyclobutyl, cyclopentyl, cyclohexyl,    R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or    tetrahydropyran-4-yl; and-   X denotes Br or I.

In a further aspect the present invention relates to compounds of theformula XXVI

wherein

-   X denotes Br or I; and-   Z denotes hydroxy, fluorine, chlorine, bromine, iodine,    C₁₋₄-alkyl-sulfonyloxy, arylsulfonyloxy,    aryl-C₁₋₃-alkyl-sulfonyloxy, di-(C₁₋₆-alkyloxy)-boronyl,    di-hydroxy-boronyl, KF₃B, NaF₃B or LiF₃B; and-   the term “aryl” is defined as hereinbefore.

In a further aspect the present invention relates to compounds of theformula XXXII

wherein

-   R¹ denotes cyclobutyl, cyclopentyl, cyclohexyl,    R-tetrahydrofuran-3-yl, S-tetrahydrofuran-3-yl or    tetrahydropyran-4-yl; and-   R² independently of one another denote hydrogen,    (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl,    aryl-(C₁₋₃-alkyl)-carbonyl, aryl-C₁₋₃-alkyl, allyl,    R^(a)R^(b)R^(c)Si, CR^(a)R^(b)OR^(c), wherein two adjacent groups R²    may be linked with each other to form a bridging group SiR^(a)R^(b),    CR^(a)R^(b) or CR^(a)OR^(b)—CR^(a)OR^(b);-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, while the alkyl groups may be mono- or    polysubstituted by halogen;-   L1 independently of one another are selected from among fluorine,    chlorine, bromine, C₁₋₃-alkyl, C₁₋₄-alkoxy and nitro;-   while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups, which may be mono- or polysubstituted with L1.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the groups, residues and substituents,particularly R¹, R², R³, R′, R^(a), R^(b), R^(c), L1, M, X and Z, aredefined as above and hereinafter.

If residues, substituents or groups occur several times in a compound,they may have the same or different meanings.

In the processes and compounds according to this invention the followingmeanings of groups and substituents are preferred:

-   R¹ preferably denotes R-tetrahydrofuran-3-yl or    S-tetrahydrofuran-3-yl.-   R² preferably denotes hydrogen, methylcarbonyl, ethylcarbonyl or    trimethylsilyl.-   R^(a), R^(b), R^(c) independently of one another preferably denote    methyl, ethyl, n-propyl or i-propyl, tert.-butyl or phenyl; most    preferably methyl.-   R′ preferably denotes hydrogen, methyl or ethyl.

In the following the processes according to this invention are describedin detail.

The Scheme 0 depicts the conversion of compound II to compound I viaremoval of the protective groups R² not being hydrogen present incompound II, wherein R¹, R² and R³ are defined as hereinbefore.

Any acyl protecting group R² used is cleaved for example hydrolyticallyin an aqueous solvent, e.g. in water, isopropanol/water, aceticacid/water, tetrahydrofuran/water or dioxane/water, in the presence ofan acid such as trifluoroacetic acid, hydrochloric acid or sulphuricacid or in the presence of an alkali metal base such as lithiumhydroxide, sodium hydroxide or potassium hydroxide or aprotically, e.g.in the presence of iodotrimethylsilane, at temperatures between 0 and120° C., preferably at temperatures between 10 and 100° C.

A trifluoroacteyl group R² is preferably cleaved by treating with anacid such as hydrochloric acid, optionally in the presence of a solventsuch as acetic acid at temperatures between 50 and 120° C. or bytreating with sodium hydroxide solution optionally in the presence of asolvent such as tetrahydrofuran or methanol at temperatures between 0and 50° C.

Any acetal or ketal protecting group R² used is cleaved for examplehydrolytically in an aqueous solvent or aqueous mixture of solvents,e.g. in water, isopropanol/water, acetic acid/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid oraprotically, e.g. in the presence of iodotrimethylsilane, attemperatures between 0 and 120° C., preferably at temperatures between10 and 100° C.

A silyl group R², for example trimethylsilyl, is cleaved for example inwater, an aqueous solvent mixture or a lower alcohol such as methanol orethanol in the presence of a base such as lithium hydroxide, sodiumhydroxide, potassium carbonate or sodium methoxide.

In aqueous or alcoholic solvents, acids such as e.g. hydrochloric acid,trifluoroacetic acid or acetic acid are also suitable. For cleaving inorganic solvents, such as for example diethyl ether, tetrahydrofuran ordichloromethane, it is also suitable to use fluoride reagents, such ase.g. tetrabutylammonium fluoride.

A benzyl, methoxybenzyl or benzyloxycarbonyl group R² is advantageouslycleaved hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0 and 100° C., but preferably at ambient temperatures between 20and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group R² is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane optionally using a solvent suchas methylene chloride, dioxane, methanol or diethylether.

The glucose derivatives of formula II may be synthesized via reductionof the anomeric carbon-oxygen bond of compound III (Scheme 1).

R′ and R¹ are defined as hereinbefore. R² is defined as hereinbefore andrepresents for example hydrogen, acteyl, pivaloyl, benzoyl,tert-butoxycarbonyl, benzyloxycarbonyl, trialkylsilyl, benzyl orsubstituted benzyl. In case two adjacent groups R² are linked with eachother to form a bridging group they preferably form an acetal such ase.g. benzylideneacetal, a ketal such as e.g. isopropylideneketal, or anethylene group that results in the formation of a dioxane such as e.g.the combination with 2,3-dimethoxy-butylene which is linked via position2 and 3 of the butylene group to the oxygen atoms of the pyranose. Apreferred meaning of R² is hydrogen or tri-(C₁₋₃-alkyl)silyl, such astrimethylsilyl or triisopropylsilyl. R′ preferably denotes hydrogen orC₁₋₄-alkyl, in particular methyl or ethyl.

The reduction may be conducted with a reducing agent in the presence ofor without a Lewis acid. Suitable reducing agents include for examplesilanes such as e.g. triethylsilane, tripropylsilane,triisopropylsilane, or diphenylsilane, sodium borohydride, sodiumcyanoborohydride, zinc borohydride, borane complexes, lithium aluminumhydride, diisobutylaluminum hydride, or samarium iodide. Suitable Lewisacids are such as e.g. boron trifluoride etherate, trimethylsilyltriflate, titanium tetrachloride, tin tetrachloride, scandium triflate,copper(II) triflate, or zinc iodide; or suitable Lewis acids areBrønsted acids such as e.g. hydrochloric acid, toluenesulfonic acid,trifluoroacetic acid, or acetic acid. Depending on the reducing agentthe reductions may be carried out without a Lewis acid. The reaction maybe carried out in a solvent such as for example methylene chloride,chloroform, acetonitrile, toluene, hexane, diethylether,tetrahydrofuran, dioxane, ethanol, water, or mixtures thereof. Thesolvent is preferably selected in view of the reducing agent and theoptional Lewis acid. Preferred reaction temperatures are between −80° C.and 120° C., more preferably between −30 and 80° C.

One particularly suitable combination of reagents consists for exampleof triethylsilane and boron trifluoride etherate, which is convenientlyused in acetonitrile, dichloromethane, or mixtures thereof attemperatures from −60° C. to 60° C.

The reduction is preferably carried out in the absence of water, inparticular with a content of water in the reaction mixture below 2000ppm, even more preferably below 1000 ppm.

In addition to the reducing agents mentioned above, hydrogen may be usedfor the reduction intended. This transformation may be accomplished inthe presence of a transition metal catalyst such as e.g. palladium oncharcoal, palladium oxide, platinum oxide, or Raney nickel, in solventssuch as e.g. tetrahydrofuran, ethyl acetate, methanol, ethanol, water,or acetic acid at temperatures of −40° C. to 100° C. and at hydrogenpressures of 1 to 10 Torr.

The glucose derivatives of formula III may be synthesized fromD-gluconolactone or a derivative thereof by reacting the desiredbenzylbenzene compound in the form of an organometallic compound (Scheme2a).

The Scheme 2a and the following sections describe preferred conditionsand embodiments of the process according to the third aspect of thisinvention.

The Grignard or Lithium reagent of benzylbenzene (VI) may be preparedfrom the corresponding brominated or iodinated benzylbenzene V eithervia a so-called halogen-metal exchange reaction or by inserting themetal into the carbon-halogen bond. The halogen-metal exchange tosynthesize the corresponding lithium compound VI may be carried out forexample with an organolithium compound such as e.g. n-, sec- ortert-butyllithium. A preferred amount of the organolithium compound isin the range from about 1 to 2 mol, more preferably about equimolar withrespect to the benzylbenzene V.

The analogous magnesium compound may also be generated by ahalogen-metal exchange with a suitable Grignard reagent such asC₃₋₄-alkylmagnesium chloride or bromide, for example isopropyl- orsec-butylmagnesium bromide or chloride or diisopropyl- ordi-sec-butylmagnesium without or in the presence of an additional saltsuch as e.g. lithium chloride that may accelerate the metalationprocess. The specific transmetalating organomagnesium compound may alsobe generated in situ from suitable precursors (see e.g. Angew. Chem.2004, 116, 3396-3399 and Angew. Chem. 2006, 118, 165-169 and referencesquoted therein). The Grignard reagent is preferably used in an amount inthe range from about 1 to 5 mol per mol of the benzylbenzene V.

The halogen-metal exchange reactions are preferably carried out between−100° C. and 40° C., particularly preferably between −80° C. and 10° C.A more preferred temperature range in the halogen-lithium exchangereaction is −80° C. and −15° C.

Preferably the halogen-metal exchange reaction is carried out in aninert solvent or mixtures thereof, such as for example diethylether,dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, toluene,hexane, dimethylsulfoxide, dichloromethane or mixtures thereof.Particularly preferred solvents are selected form among tetrahydrofuran,diethylene glycol dimethyl ether, hexane and mixtures thereof.

The magnesium or lithium derivatized compounds thus obtained mayoptionally be transmetalated with metal salts such as e.g. ceriumtrichloride, zinc chloride or bromide, indium chloride or bromide, toform alternative organometal compounds (VI) suitable for addition.

Alternatively, the organometal compound VI may also be prepared byinserting a metal into the carbon-halogen bond of the haloaromaticcompound V. Lithium or magnesium are suitable elemental metals for thistransformation. The insertion can be achieved in solvents such as e.g.diethylether, dioxane, tetrahydrofuran, toluene, hexane,dimethylsulfoxide and mixtures thereof at temperatures ranging from −80to 100° C., preferably at −70 to 40° C. In cases in which no spontaneousreaction takes place prior activation of the metal might be necessarysuch as e.g. the treatment with 1,2-dibromoethane, iodine,trimethylsilylchloride, acetic acid, hydrochloric acid and/orsonication.

The addition of the organometal compound VI to gluconolactone orderivatives thereof (IV) is preferably carried out at temperaturesbetween −100° C. and 40° C., particularly preferably at −80 to −10° C.,in an inert solvent or mixtures thereof, to obtain the compound offormula III. In case the compound VI is a lithiumorganic compound theaddition is even more preferably carried out at temperatures in therange from −80 to −20° C. In case the compound VI is a magnesiumorganiccompound particularly preferred temperatures during the addition are inthe range from −30° C. to −15° C.

All foregoing reactions may be performed in air though the executionunder inert gas atmosphere is preferred. Argon and nitrogen arepreferred inert gases.

The metalation and/or coupling reaction may also be carried out inmicroreactors and/or micromixers which enable high exchange rates; forexample analogously to the processes described in WO 2004/076470.

Suitable solvents for the addition of the metalated compound VI to theappropriately protected gluconolactone IV are e.g. diethylether,toluene, methylene chloride, hexane, tetrahydrofuran, dioxane,N-methylpyrrolidone and mixtures thereof.

The addition reactions may be carried out without any further adjuvantsor in the presence of a promoter such as e.g. BF₃*OEt₂ or Me₃SiCl whichmay be advantageous in the case of sluggishly reacting coupling partners(see M. Schlosser, Organometallics in Synthesis, John Wiley & Sons,Chichester/New York/Brisbane/Toronto/Singapore, 1994).

Preferred definitions of the substituents R² in Scheme 2a are benzyl,substituted benzyl, trialkylsilyl, particularly preferablytri-(C₁₋₃-alkyl)silyl, such as trimethylsilyl, triisopropylsilyl,4-methoxybenzyl and benzyl. If two adjacent substituents R² are linkedtogether, these two substituents are preferably part of abenzylideneacetal, 4-methoxybenzylideneacetal, isopropylketal orconstitute a dioxane with 2,3-dimethoxy-butylene which is linked via the2 and 3 positions of the butane with the adjacent oxygen atoms of thepyranose. The group R′ preferably denotes hydrogen, C₁₋₄-alkyl,C₁₋₄-alkylcarbonyl or C₁₋₄-alkyloxycarbonyl, particularly preferablyhydrogen, methyl or ethyl.

The group R′ is introduced after the addition of the organometalliccompound VI or a derivative thereof to the gluconolactone IV. If R′equals hydrogen or C₁₋₄-alkyl the reaction solution is treated with analcohol, in particular an C₁₋₄-alkanol, such as e.g. methanol or ethanolor water in the presence of an acid such as e.g. acetic acid,methanesulfonic acid, toluenesulfonic acid, sulfuric acid,trifluoroacetic acid, or hydrochloric acid. This reaction with thealcohol or water is preferably carried out at temperatures in the rangefrom about 0° C. to 80° C., particularly from about 20° C. to 60° C.During installing R′ the protective groups R² may be cleaved if labileunder the reaction conditions employed resulting in the correspondingprotonated compound, i.e. compound III in which R² equals H. For exampleprotecting groups wherein R² denotes trialkylsilyl, such astrimethylsilyl, are usually cleaved when the reaction solution istreated with an alcohol and/or water in the presence of an acid so thata compound III is obtained wherein R² denotes H.

R′ may also be attached after preparation of the hydrogen compound III(R′═H) by reacting the anomeric hydroxyl group with a suitableelectrophile such as e.g. methyl iodide, dimethyl sulfate, ethyl iodide,diethyl sulfate, acteyl chloride, or acetic anhydride in the presence ofa base such as e.g. triethlyamine, ethyldiisopropylamine, sodium orpotassium or cesium carbonate, sodium or potassium or cesium hydroxide.The hydroxyl group can also be deprotonated prior to the addition of theelectrophile with e.g. sodium hydride.

Approach 2 depicted in Scheme 2b illustrates the synthesis of theC-glucosides commencing with an appropriately protected D-glucal XXX(see Synlett 2004, pp. 1235-1238; Org. Lett. 2003, 5, pp. 405-2408 andreferences quoted therein for analogous approaches). The protectedD-glucal XXX is metallated to yield the D-glucal derivative XXXI whereinM denotes a lithium, magnesium, zinc, indium, boron, tin, silicon orchromium moiety; in particular lithium, magnesium halide, zinc halide,indium halide, boronic acid, boronic acid ester. Metalation of glucalXXX at C-1 may be accomplished by deprotonation with a strong base.Strong bases capable of deprotonating the glucal may be lithium basessuch as e.g. n-butyl lithium, sec-butyl lithium or tert-butyl lithium.The C-1 lithiated glucal thus obtained may be transmetalated withdifferent electrophilic metal sources delivering the corresponding C-1metalated glucal derivative. Metal species suitable for the subsequenttransformation, coupling with the aglycon moiety, are derived from e.g.lithium, magnesium, zinc, indium, boron, tin, silicon, and chromium. Thetransmetalation of the glucal compound from lithium to one of the metalsmentioned may be conducted with the corresponding e.g. halides such aschloride, bromide and iodide, sulfonates such as e.g.trifluoromethanesulfonate, and alcoxides such as e.g. methoxide,ethoxide, propoxide and isopropoxide of the metal species to beintroduced. Depending on the metal transmetalated to the metal may bearmore than one glucal residue such as in the corresponding triglucalindium or diglucal zinc. The corresponding monoglucal substituted metalderivatives are employable as well. The metalation of glucal with astrong base, in particular a lithium base, is preferably performed ininert solvents such as e.g. tetrahydrofuran, ether, dioxane,dimethoxyethane, hexane, and toluene. Preferred temperatures are in therange between −80° C. and 50° C. The transmetalation may be conducted inthe same solvents depending on the electrophilic metal species in thesame temperature range. Among the electrophilic metal species usable inthe transmetalation the following are among the most appropriate:trialkylchlorostannane, tetrachlorostannane, trialkylchlorosilane,trialkoxychlorosilyl chloride or bromide, boron trichloride, trialkylborates, dialkylchloroborane, indium trichloride, zinc chloride,triflate or bromide, magnesium chloride or bromide. This compilation isby no means meant to restrict the employable metal electrophiles to theones mentioned but is supposed to give an idea of electrophiles that canbe used. In the above and below described reactions the protectinggroups R² are preferably chosen in view of their stability under basicconditions, in particular the groups R² independently of each otherdenote —SiR^(a)R^(b)R^(c), wherein two adjacent groups R² may be linkedwith each other to form a bridging group SiR^(a)R^(b), wherein R^(a),R^(b), R^(c) are defined as hereinbefore, preferably denote isopropyl.

The metalated glucal derivative of the formula XXXI thus obtained may becoupled with the agylcon V wherein the group X denotes a leaving group,preferably selected from the group consisting of chlorine, bromine,iodine, sulfonate such as e.g. trifluoromethane-sulfonate, tosylate,benezenesulfonate, and mesylate, chlorosulfonate, sulfonic acid or saltsthereof, hydroxycarbonyl or salts thereof, nitrile, and diazonium salts.The coupling reactions are preferably carried out in the presence of atransition metal catalyst such as e.g. salts, complexes or elementalmodifications of palladium, copper, iron, and nickel. Complexes can beformed in situ or prior to the addition of the transition metal to thereaction mixture. The ligands in the complexes of the transition metalmay be e.g. triarylphosphine, aryldialkyl-phosphine, trialkylphosphine,phosphite, 1,3-disubstituted dihydroimidazolium carbene,1,3-disubstituted imidazolium carbene, and alkenes. The reaction ispreferably carried out in an inert organic solvent or mixtures thereof.Suitable solvents may be e.g. tetrahydrofuran, dioxane, dimethoxyethane,hexane, toluene, benzene, dimethylformamide, dimethylacetamide,N-methylpyrrolidinone, acetone, ethyl acetate, water, methanol, ethanol,propanol, isopropanol, ethylene glycol, polyethylene glycol. Thecoupling reactions are preferably carried out between −80° C. and 180°C., more preferably at −20° C. to 120° C. The concluding synthetic stepin Scheme 2b is the formal addition of water to the double bond in theglucal moiety. This process may be done by e.g. hydroboration thatresults in the formation of the 2-boron-2-desoxy glucose derivative thatcan be converted to the corresponding glucose compound by oxidation ofthe carbon-boron bond. Suitable boranes for the hydroboration are e.g.borane or ether, thioether or amine adducts thereof, alkylboranes ordialkylboranes such as e.g. hexylborane, thexylborane, diethylborane and9-BBN, pinacolborane, catecholborane, halo or dihaloborane such as e.g.dichloroborane. The hydroboration may be conducted in e.g.tetrahydrofuran, hexane, cyclohexane, ether, toluene, benzene,dichloromethane. A preferred temperature range is between −50° C. and150° C., preferably between −20° C. and 50° C. The oxidative cleavage ofthe carbon-boron bond may be performed with an oxidizing reagent such ase.g. hydrogen peroxide, tert-butyl hydrogen peroxide, sodium perborate,and trialkylamine N-oxide. Depending on the oxidizing reagent thereaction is advantageously carried out in the presence of a base such ase.g. sodium hydroxide. The reaction is preferably carried out in aninert organic solvent or mixtures thereof. Preferred solvents areselected from among tetrahydrofuran, water, alcohols, dioxane,diemethoxyethane, cyclohexane, hexane, toluene, dichloromethane andmixtures thereof. A preferred temperature range is between −30 to 150°C., preferably between 0 to 110° C. An alternative to the hydroborationin order to add water to the double bond is the combination ofepoxidation or dihydroxylation of the double bond and reduction of theresultant anomeric carbon-oxygen bond. Suitable oxidizing reagents forthe epoxidation are e.g. dimethyldioxirane, trifluordimethyldioxirane,3-chloroperoxybenzoic acid, hydrogen peroxide and oxygen in the presenceof a transition metal catalyst. Another suitable oxidizing agent isperoxomonosulfuric acid, peroxodisulf uric acid and salts thereof, inthe presence of at least one ketone, in particular triple salts of theformula 2 KHSO₅×KHSO₄×K₂SO₄ which are commercially available, forexample under the brand names OXONE® (trademark E.I. du Pont de Nemours)and CAROAT® (trademark Degussa, Peroxid-Chemie GmbH & Co. KG,Dr.-Gustav-Adolph-Str. 3, D-82049 Pullach, Germany) in combination witha ketone, preferably acetone. Dihydroxylation can be accomplished withe.g. osmium tetroxide and dipotassium osmium tetroxide preferably in thepresence of a co-oxidant such as e.g. potassium hexacyano-ferrate,hydrogenperoxide, and N-methylmorpholine N-oxide; hydrolytic opening ofthe oxirane resulting from the epoxidation gives also access to thedihydroxylation product. The oxidations may be conducted in inertorganic solvents or mixtures thereof such as e.g. dichloromethane,tetrahydrofuran, ether, hexane, cyclohexane, dioxane, acetone, ethylacetate, acetonitrile, water, alcohols and mixtures thereof. A preferredtemperature range is between −80° C. and 100° C., preferably between−50° C. and 50° C. Reduction of the anomeric carbon-oxygen bond of theoxirane or dihydroxylation product may be accomplished with reducingagents such as e.g. trialkylsilanes such as e.g. triethylsilane,borohydrides such as e.g. sodium borohydride and aluminum hydrides suchas e.g. diisobutylaluminum hydride. Depending on the reducing agent thepresence of a Lewis acid such as e.g. boron trifluoride etherate, zincchlorides, trimethylsilyl chloride or triflate, alkyl-, dialkyl- oraluminum halide, copper triflate, and Brønsted acids such as e.g.hydrochloric acid, acetic acid, alkyl- or arylsulfonic acids,trifluoroacetic acid is necessary or at least advantageous.Dichloromethane, acetonitrile, tetrahydrofuran, ether, hexane are amongthe preferred solvents. A preferred temperature range is between −80° C.and 120° C. Hydrogen in combination with a transition metal catalystsuch as e.g. palladium on carbon, Raney-nickel, and palladium hydroxidemay be used as well.

Subsequently, the product of the formula XXXIII may be transferred intothe product of the formula I by cleaving, in particular hydrolysing, theprotective groups R² not being hydrogen, advantageously employingmethods as described hereinbefore.

Scheme 2c illustrates an alternative access to C-glucosides startingfrom the glucal XXX (see e.g. Synlett 2003, pp. 870-872; Tetrahedron2002, 58, pp. 1997-2009 and references quoted therein for analogousapproaches). Epoxidation with an appropriate oxidizing reagenttransforms the glucal XXX into the corresponding glucaloxide XXXIV.Suitable reaction conditions for this transformation have already beendescribed for the analogous conversion of glucal XXXII shown in Scheme2b. Among the oxidizing agents described there dimethyldioxirane andtrifluorodimethyldioxirane generated separately or in situ arepreferred. Said oxidizing agents may be obtained with e.g.peroxomonosulf uric acid, peroxodisulf uric acid and salts thereof, inthe presence of at least one ketone, in particular with triple salts ofthe formula 2 KHSO₅×KHSO₄×K₂SO₄ which are commercially available, forexample under the brand names OXONE® (trademark E.I. du Pont de Nemours)and CAROAT® (trademark Degussa, Peroxid-Chemie GmbH & Co. KG,Dr.-Gustav-Adolph-Str. 3, D-82049 Pullach, Germany) in combination witha ketone, preferably acetone. The reaction is preferably carried out attemperatures in the range between −80 and 0° C. in an inert organicsolvent or mixtures thereof. Preferred solvents are selected from thegroup consisting of dioxan, 1,2-dimethoxyethane, toluene, hexane,tetrahydrofuran, diethylether, dichloromethane and mixtures thereof. Inthe above and below described reactions the protecting groups R² arepreferably independently of each other selected from the groupconsisting of C₁₋₄-alkylcarbonyl, C₁₋₄-alkyloxycarbonyl, arylmethyl andR^(a)R^(b)R^(c)Si, wherein aryl, R^(a), R^(b) and R^(c) are defined ashereinbefore.

The ensuing reaction, epoxide opening with a metalated aglycon of theformula VI in which M denotes a lithium, magnesium, zinc, indium,aluminum or boron moiety, affords the desired C-glucoside. For thistransformation the preferred meaning of M is lithium, magnesium halide,zinc halide, indium halide, aluminum halide, dialkylaluminum halide orboronic acid compound. The synthesis of the lithium or magnesiumderivative of compound VI has been detailed in Scheme 2a, whereas thetransmetalation of these compounds to one of the alternative metalspecies may be done in analogy to the transmetalation of the lithiatedglucal to the same metal derivatives presented in Scheme 2b. The epoxideopening reaction may take place without an adjuvant or in the presenceof a transition metal salt or complex such as e.g. copper cyanide orhalide or in the presence of a Lewis acid such as e.g. borontrifluorideetherate or trimethylsilyl-chloride or triflate. Suitable inert solventsmay be e.g. acetone, ether, tetrahydrofuran, acetonitrile,dichloromethane, toluene, hexane and mixtures thereof. A preferredtemperature range is between −80° C. to 60° C.

Subsequently the product of the formula XXXIII may be transferred intothe product of the formula I by cleaving, in particular hydrolysing, theprotective groups R² not being hydrogen, advantageously employingmethods as described hereinbefore.

A glucose derivative XXXV bearing a potential leaving group Hal at theanomeric carbon may be utilized as starting material for the couplingwith a metalated aryl aglycon VI as well (see J. Carbohydr. Chem. 1994,13, pp. 303-321 and references quoted therein for analogous approaches).Suitable leaving groups Hal may be halides, alcoxides, acyl groups suchas carboxylates and carbonates; in particular F, Cl, Br,C₁₋₃-alkylcarbonyloxy, C₁₋₃-alkyloxy-carbonyloxy or C₁₋₃-alkyloxy, suchas e.g. Cl, Br, methoxide, acetate and methylcarbonate. Suitable metalsM attached to the aryl part are e.g. lithium, magnesium as e.g.magnesium halide, zinc as e.g. zinc halide, indium as e.g. indiumdihalide, boron as e.g. boronic acid or boronic acid ester. Thepreparation of these metalated aryl compounds from the correspondinghalogenated aromats has been described in Scheme 2c. The substitutionreactions can be run without or in the presence of an additional Lewisacid such as e.g. boron trifluoride etherate, trimethylsilyl chloride ortriflate depending on the metal species and glucosyl donor employed. Thereaction is preferably carried out in an inert organic solvents ormixtures thereof. The preferred solvent is preferably chosen in view ofthe metalated aglycon, glucosyl donor and adjuvants needed; thefollowing solvents may be advantageous: tetrahydrofuran, dioxane,toluene, hexane, ether, N-methylpyrrolidinone, dimethylacetamide,dimethylformamide, acetonitrile, dichloromethane and mixtures thereof.The coupling reaction is usually conducted between −80° C. and 120° C.,preferably at −60° C. to 60° C. In the above and below describedreactions the protecting groups R² are preferably independently of eachother selected from the group consisting of C₁₋₄-alkylcarbonyl,C₁₋₄-alkyloxycarbonyl, arylmethyl and R^(a)R^(b)R^(c)Si, wherein aryl,R^(a), R^(b) and R^(c) are defined as hereinbefore.

Subsequently the product of the formula II may be transferred into theproduct of the formula I by cleaving, in particular hydrolysing, theprotective groups R² not being hydrogen, advantageously employingmethods as described hereinbefore.

The synthesis of haloaromatic compound V may be carried out usingstandard transformations in organic chemistry or at least methods knownfrom the specialist literature in organic synthesis (see inter alia J.March, Advanced Organic Reactions, Reactions, Mechanisms, and Structure,4th Edition, John Wiley & Sons, Chichester/New

York/Brisbane/Toronto/Singapore, 1992 and literature cited therein). Thesynthesis strategies described in the following provide a demonstrationof this, by way of example.

In the following schemes

-   X denotes bromine or iodine,-   Alk denotes C₁₋₄-alkyl,-   R denotes C₁₋₄-alkyl, C₁₋₄-alkoxy, CF₃, aryl or aryl-C₁₋₃-alkyl,    wherein aryl-groups may be mono- or polysubstituted with L1;-   R¹ is as defined hereinbefore; and-   L1 is as defined hereinbefore;-   unless indicated otherwise.

Scheme 3 displays the synthesis of aglycon V starting from benzophenonederivative IX that can be prepared from a benzoic acid derivative and aphenylalkylether or a metalated phenylalkylether (see Schemes 5, 8, and9). The first step is the cleavage of the ether moiety in compound IXthat can be accomplished under neutral, acidic and basic conditions.Suitable acidic reagents for this transformation are e.g. borontrichloride or tribromide or triiodide, trimethylsilyl iodide, aluminumchloride or bromide, hydrobromic acid, hydrochloric acid, ceriumchloride, trifluoroacetic acid, and trifluoromethylsulfonic acid thatmay be used in concert with a nucleophile such as e.g. metal halidessuch as e.g. sodium iodide, water, alkylthiols, thioanisole, anddialkylsulfides, that may scavenge the departing alkyl group. Dependingon the acid used solvents selected from the group consisting ofhalogenated hydrocarbons, such as e.g. dichloromethane, chloroform or1,2-dichloroethane, acetonitrile, toluene, hexane, acetic acid andcombinations thereof are preferred. Reactions without additional solventare also feasible. The reactions are generally carried out at −90 to150° C., preferably at −80 to 50° C. Cleavage under neutral or basicconditions can be done e.g. with metal thiolates such as e.g. sodiumsulfide, sodium ethanethiolate, sodium trimethylsilyl-thiolate,potassium thiophenolate, sodium cyanide, and lithium iodide in solventssuch as e.g. dimethylformamide, dimethylacetamide,1,3-dimethyl-2-oxohexahydropyrimidine, N-methyl-pyrrolidone,tetrahydrofuran, collidine, and quinoline at temperatures between 0 and250° C., preferably at 50 to 180° C. The second step outlined in Scheme3 comprises the attachment of residue R¹ to the phenolic oxygen ofcompound VIII. This transformation can be carried out under basicconditions as classical nucleophilic substitution reaction. Accordingly,the phenol is deprotonated by a base to from the correspondingphenolate. Suitable bases are e.g. group I or II metal salts, inparticular carbonates, hydroxides, alkoholates such as e.g. methoxide,ethoxide or tertbutoxide, and metal hydrides such as e.g. sodiumhydride. The reaction can be conducted in polar and non-polar solventsas well as without solvent, preferably in alcohols such as e.g. ethanol,isopropanol or butanol, acetone, water, dimethylformamide,dimethylacetamide, N-methylpyrollidone, dimethylsulfoxide,tetrahydrofuran, dichloromethane and mixtures thereof. The phenolateobtained then is reacted with an electrophile of R¹ at temperaturesbetween 20 and 180° C., preferably between 40 and 120° C. Suitableelectrophiles of R¹ are e.g. halides, such as chlorides, bromides oriodides, alkylsulfonates such as e.g. methylsulfonate,trifluoromethanesulfonate, arylsulfonates such as e.g.4-bromophenylsulfonate, 4-methylphenylsulfonate or phenylsulfonate. Analternative approach to attach R¹ to the phenol VIII is the addition ofthe phenol VIII to a group R¹ that bears an appropriately situated C═Cdouble bond. This reaction may be conducted in the presence of aBrønsted acid such as e.g. trifluoro-methanesulfonic acid, hydrochloricacid, sulfuric acid, or a transition metal catalysts such as e.g.platinum, ruthenium, palladium, or gold salts or complexes thereof;preferred salts are triflate, chloride, bromide and iodide (see e.g.Cai-Guang Yang and Chuang He; J. Am Chem. Soc. 2005, 127, and referencesquoted therein). The solvent most appropriate for the addition dependson the acid or transition metal that is employed. Solvents such as e.g.toluene, benzene, dichloromethane, 1,2-dichloroethane, acetonitrile,tetrahydrofuran, dimethylacetamide, N-methylpyrrolidone, hexane, andethyl acetate may be suited. The reaction is carried out at 0 to 200°C., preferably at 20 to 140° C. Scheme 3 concludes with the reduction ofbenzophenone VII to furnish aglycon V. Proper reducing agents for thisconversion are e.g. silane such as e.g. Et₃SiH and triisopropylsilane,borohydride such as e.g. NaBH₄, and aluminum hydride such as e.g. LiAlH₄in the presence of a Lewis acid such as for example BF₃*OEt₂,tris(pentafluorophenyl)borane, trifluoroacetic acid, hydrochloric acid,aluminum chloride, or InCl₃. The reactions are preferably carried out insolvents such as e.g. halogenated hydrocarbons such as dichloromethaneand 1,2-dichloroethane, toluene, benzene, hexane, acetonitrile andmixtures thereof at temperatures of −30 to 150° C., preferably at 20 to100° C. Reductions with hydrogen in the presence of a transition metalcatalyst such as e.g. Pd on charcoal are another possible method ofsynthesis but might be less suited here due to competing reductionprocesses in the rest of the molecule. Reductions according toWolff-Kishner or variants thereof are also conceivable. Hence, theketone is converted with hydrazine or a derivative thereof such as e.g.1,2-bis(tert-butyldimethylsilyl)hydrazine into the hydrazone whichbreaks down under strongly basic reaction conditions and heating toliberate the diphenylmethane V and nitrogen. The reaction may be carriedout in one pot or after isolation of the hydrazone or a derivativethereof in two separate reaction steps. Suitable bases include e.g. KOH,NaOH or KOtBu in solvents such as e.g. ethyleneglycol, toluene, DMSO,2-(2-butoxyethoxyl)ethanol or tert-butanol; solvent-free reactions arealso possible. The reactions may be performed at temperatures between 20and 250° C., preferably between 80 and 200° C. An alternative to thebasic conditions of the Wolff-Kishner reduction is the Clemmensenreduction which takes place under acidic conditions, which may also beused here if no concurrent dehalogenation occurs.

Scheme 4 outlines a slightly different approach to the synthesis ofaglycon V compared with Scheme 3. Nevertheless, the ether cleavage andthe ensuing etherification delineated in Scheme 4 can principally becarried out under reaction conditions analogous to the synthesisdescribed above with respect to the compounds VIII and VII.

Scheme 5 describes the assembly of aglycon V starting from the knownbenzoyl chloride XII and phenylether derivative XIII. The first step,the preparation of benzophenone VII, can be characterized asFriedel-Crafts or Friedel-Crafts-type acylation, a well-known and widelyused method in organic synthesis. In principal, the benzoyl chloride XIImay be replaced by other benzoic acid derivatives such as e.g. benzoylanhydrides, esters, or benzonitriles. This classic reaction has a widesubstrate scope and is commonly carried out in the presence of acatalyst such as e.g. AlCl₃, FeCl₃, iodine, iron, ZnCl₂, sulfuric acid,or trifluoromethanesulfonic acid which is used in catalytic orstoichiometric amounts. The reactions are preferentially performed inchlorinated hydrocarbons such as e.g. dichloromethane or1,2-dichloroethane, in hydrocarbons such as e.g. hexane at temperaturesranging from −30 to 140° C., preferably at 30 to 100° C. However, othersolvents and solvent mixtures and also solvent-free reactions orreactions in a microwave oven are also possible. The second reactionstep in Scheme 5 is analogous to the final reaction in Scheme 3 asdescribed hereinbefore.

Scheme 6 illustrates an alternative synthesis of the aglycon V via aFriedel-Crafts-type alkylation of phenylether XIII with benzylelectrophile XIV (see Angew. Chem. 2005, 117, pp. 242-246 and Syn.Commun. 2004, 34, pp. 3161-3165 and references quoted therein). Thereaction is commonly conducted in the presence of a catalyst, inparticular of a Lewis acid such as e.g. scandium chloride, zincchloride, aluminium chloride or boron trifluoride, of a Brønsted acidsuch as e.g. sulfuric acid, hydrochloric acid or hydrogenfluoride, of alanthanide salt such as e.g. cerium sulfate or ytterbium chloride, of anactinide salt, of a transition metal salt or of a complex such as e.g.IrCl₃*nH₂O, RhCl₃*nH₂O, H₂[PtCl₆]*6H₂O or H₂[PdCl₆]*6H₂O. The catalystscan be applied in stoichiometric or excess quantities though in manycases substoichometric or even catalytic amounts are sufficient. Thereactions are usually carried out with an excess of aromatic compoundXIII relating to the benzyl electrophile without solvent; though inertsolvents such as e.g. halogenated hydrocarbons or hydrocarbons can beemployed as well. The reaction is generally conducted at temperaturesbetween 0 and 200° C., preferably at 20 to 140° C.

The approach presented in Scheme 7 starts with the synthesis ofphenylether XVI from monosubstituted phenol XV that can be conductedanalogously to the synthesis of the etherification shown in Scheme 3. Inthe second step of Scheme 7 the residue Z² is exchanged for a metal orsubstituted metal residue. Lithium or magnesium substituted aromaticcompounds XVII may be prepared from chlorinated, brominated, oriodinated aromatic compounds XV in the same manner as for the metalatedaglycon VI described in Scheme 2a. The corresponding boron substitutedcompound such as e.g. boronic acid, boronic acid ester, ordialkylarylborane is accessible from these metalated phenyl groups XVIIby the reaction with an appropriate boron electrophile such as e.g.boronic acid ester, haloboronic acid ester, alkylbornic acid ester,dialkylboronic acid ester, trihaloborane, and derivatives thereof. Inaddition, the boronylated aromatic compound XVII may also be preparedfrom the corresponding chlorinated, brominated, iodinated, orpseudohalogenated such as e.g. trifluoromethanesulfonated and tosylatedprecursor and a diboron compound such e.g. bis(pinacolato)diboron andbis(neopentyl-glycolato)diboron, or a borane such as e.g. pinacolboranethrough a transition metal catalyzed reaction (see e.g. TetrahedronLett. 2003, p. 4895-4898 and references quoted therein). The transitionmetal is e.g. palladium that is employed as element, salt, or complex;common Pd sources are e.g. palladium on charcoal, palladium acetate,palladium chloride, palladium bromide, palladium dibenzylideneacetonethat are used as such or in combination with a ligand such as e.g.phosphines such as e.g. tricyclohexylphosphine, triphenylphosphine,1,1′-bis(diphenyl-phosphino)ferrocene, and tritolylphosphine, orphosphites or imidazolium salts such as 1,3-diaryl or dialkylimidazoliumhalides or pseudohalides or dihydroimidazolium salts. The resultingcomplex of the transition metal and the ligand may be prepared in situor in a separate step. The reactions are preferably conducted in thepresence of a base such as e.g. triethylamine, potassium acetate,potassium carbonate, potassium phosphate, sodium hydroxide,triethylamine or ethyldiisopropylamine, in solvents such as e.g.acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide,dimethylacetamide, N-methyl-pyrrolidone, dioxane, toluene and mixturesthereof at 0 to 180° C., preferably at 60 to 140° C. The lithium ormagnesium substituted phenyl compounds XVII add spontaneously tobenzaldehyde XVIII furnishing diarylmethanol XIX. This reaction can beperformed in solvents such as diethylether, tetrahydrofuran, toluene,dichloromethane, dioxane, hydrocarbons such as e.g. hexane and mixturesthereof at temperatures ranging from −100 to 20° C., preferably at −80at 0° C. Aryl boronic acids XVII can be added to the benzaldehydederivative XVIII by means of a rhodium catalyzed reaction furnishing therespective diarylmethanol XIX (see e.g. Adv. Synth. Catal. 2001, p.343-350 and references quoted therein). The concluding step in Scheme 7is the reduction of the diarylmethanol XIX to the aglycon V. Suitablereducing agents for this transformation are e.g. NaBH₄, LiAlH₄, iBu₂AlH,Et₃SiH, iPr₃SiH or Ph₂SiClH. The reaction is usually carried out in thepresence of a Lewis acid such as for example BF₃*OEt₂, trifluoroaceticacid, hydrochloric acid, InCl₃, or AlCl₃ in a solvent such ashalogenated hydrocarbons such as e.g. dichloromethane or1,2-dichloro-ethane, toluene, hydrocarbons such as e.g. hexane,acetonitrile or mixtures thereof at temperatures of −80 to 150° C.,preferably at −20 to 100° C. Reductions with hydrogen in the presence ofa transition metal catalyst such as e.g. Pd on charcoal are principallyalso possible though particular care has to be taken using this methodto preserve full integrity of the rest of the molecule.

The synthesis sketched in Scheme 8 begins with the addition of metalatedphenylether derivative XXI to benzoic acid or a derivative thereof (XX)such as benzoic acid esters, benzoic acid anhydrides, benzamides such ase.g. of the Weinreb type, benzonitriles, or benzoyl chlorides to deliverthe benzophenone VII. Lithium or magnesium derivatized phenylethers XXIcan principally be added to benzamides, benzoic acid esters, benzoylchlorides, benzoic acid anhydrides, and benzonitriles to give thedesired benzophenone VII while only lithiated phenylethers react withbenzoic acids to produce the same compound. The latter reaction can becarried out in e.g. tetrahydrofuran, dioxane, diethylether, benzene,toluene, hexane and mixtures thereof at −80 to 100° C., preferably at−30 to 40° C. Benzonitriles and benzamides such as e.g. thecorresponding Weinreb-type amide or a close derivative thereof arepreferentially reacted in tetrahydrofuran, dioxane, toluene, hexane,ether and mixtures thereof at temperatures ranging from −90 to 50° C.,preferably at −80 to 20° C. Benzoyl chlorides or anhydrides and benzoicacid esters are commonly employed in inert solvents such astetrahydrofuran, diethylether, toluene, dichloromethane, dioxane,hydrocarbons such as e.g. hexane or mixtures of them at lowtemperatures, preferably at −80 to 0° C. To prevent double addition ofthe organometal compound to benzoyl chlorides, benzoyl anhydrides orbenzoic acid esters to produce the corresponding alcohol the additionmay superiorly carried out in the presence of a trapping reagent such ase.g. trimethylsilyl chloride. An alternative choice to prevent doubleaddition in the cases mentioned may be transmetalation to a lessreactive nucleophile XXI. Suitable metals are e.g. zinc, cerium,chromium, or indium that are introduced as e.g. chloride, bromide,iodide or pseudo halide salt such as e.g. trifluoromethanesulfonate totransmetalate the lithium or magnesium compound to give thecorresponding less reactive, more selective metal compound XXI. Thetransmetalation is preferentially conducted in the solvent wherein theinitial organometal compound is generated (see above) at temperatures of−90 to 0° C. Transmetalation is not restricted to the metals mentionedand the boron derivatized compounds already described in Scheme 7 butcan also furnish e.g. stannanes and silanes. Some of the transmetalatedcompounds react spontaneously with the corresponding benzoylelectrophile, particularly benzoyl chloride and anhydride, but theaddition of a transition metal catalyst may be advantageous. Inparticular arylboronic acids, esters thereof, dialkylarylboranes,aryltrifluoroborates, stannanes, silanes, indium, chromium, and zincderivatized compounds XXI couple with benzoyl chloride derivatives XXmediated by a transition metal such as e.g. palladium, copper, iron,nickel, that may be used as element or salt such as e.g. acetate,chloride, bromide, iodides, acteylacetonate, trifluoromethanesulfonate,and cyanide in combination with ligands such as e.g. phosphites,phosphines such as e.g. triphenylphosphine, tricyclohexylphoshine,tritolylphosphine, 1,3-substituted imidazolium or dihydroimidazoliumcompounds delivering diarylketones VII. The active transition metalspecies can be prepared prior to the addition to the coupling partnersbut also in the presence of the reaction partners in situ. Suitablesolvents are e.g. dimethylformamide, dimethylacetamide,N-methylpyrrolidone, dimethylsulfoxide, dioxane, ether, hexane, toluene,tetrahydrofuran, dichloromethane or mixtures thereof that are preferablyused at −50 to 150° C., particularly preferably at 0 to 120° C. Theconcluding conversion to get to the aglycon V has been detailed aboveand can be applied analogously here.

According to the Scheme 9 the metalated aryl groups XXIII that can besynthesized as described above can also be reacted with benzylelectrophiles XXII such as e.g. benzyl chlorides, bromides, iodides,sulfonates, phosphonates, carbonates, or carboxylates affordingdiarylmethanes V. Lithium or magnesium derivatized phenyl compoundsXXIII are reacted favorably (but not always necessarily) in the presenceof a transition metal such as e.g. copper, iron, nickel, or palladium(see e.g. Org. Lett. 2001, 3, 2871-2874 and Tetrahedron Lett. 2004, p.8225-8228 and references cited therein). Usable solvents are e.g.tetrahydrofuran, dioxane, toluene, dichloromethane, hexane, ether ormixtures thereof. The range of reaction temperature is from −90 to 20°C., preferably from −80 to −20° C. The transition metal can be employedas element such as e.g. on charcoal, as salt such as e.g. acetate,acteylacetonate, cyanide, chloride, bromide, iodide,trifluoromethanesulfonate, or as complex such as e.g. withdibenzylideneacetones, phosphites, phosphines such as e.g.triphenylphosphine, tricyclohexylphoshine, and tritolylphosphine, orwith carbenes derived from e.g. 1,3-disubstituted imidazolium ordihydroimidazolium compounds. The active transition metal species can beprepared in situ in the presence of the reaction partners or prior tothe addition to the coupling partners. Arylmetal compounds XXIII bearinge.g. boron, tin, silicon, zinc, indium, chromium residue are preferablyused in combination with a transition metal catalyst. Suitable metalcompounds of these types are e.g. boronic acids, boronic acid esters,dialkylboranes, trifluoroborates, trialkylstannanes, trichlorostannanes,trialkoxysilanes, dihaloindium substituted or halozinc substitutedcompounds. The metal substituted compounds XXIII may be synthesized asdescribed before by transmetalation from the corresponding lithium ormagnesium derivatized compounds or as in the case of zinc, chromium andindium also directly from the corresponding arylchloride, bromide oriodide by insertion of the elemental metal. The coupling reaction withthe benzyl electrophile may be conducted in tetrahydrofuran,dimethylformamid, dimethylacetamid, N-methyl-pyrrolidone,dimethylsulfoxide, toluene, ether, dioxane, dichloromethane,acetonitrile, hexane, water, alcohols such as e.g. ethanol, isopropanol,or mixtures thereof at reaction temperatures of −30 to 180° C.,preferably at 20 to 150° C. Depending on the metal an additional basesuch as e.g. triethylamine, ethyldiisopropylamine, cesium or potassiumor sodium or lithium carbonate, potassium or sodium or lithiumtertbutoxide, potassium phosphate, potassium or cesium ortetrabutylammonium fluoride, sodium hydroxide, thallium hydroxide,sodium methoxide and/or other additives such as e.g. lithium chloride,silver salts such as e.g. carbonate or oxide, tetrabutylammoniumbromide, and sodium bromide may be advantageous or even essential (e.g.M. Schlosser, Organometallics in Synthesis, John Wiley & Sons,Chichester/New York/Brisbane/Toronto, 1994 and references citedtherein).

The Scheme 10 shows the access to aglycon V via intermediate XXVI thatcan be prepared according to Scheme 8. If Z⁵ represents halogen such asF, intermediate XXVI may alternatively be prepared byFriedel-Crafts-acylation according to scheme 5. Replacement of Z⁵ incompound XXVI by O—R¹ may be achieved via different methods. In thecases in which Z⁵ preferably denotes fluorine, chlorine, iodine,trifluormethylsulfonate O—R¹ may be attached according to a nucleophilicsubstitution on an aromatic ring in which R¹—OH or an anion thereofreplaces Z⁵ in an addition/elimination sequence. The reaction is usuallyconducted in solvents such as e.g. dimethylformamide, dimethylacetamide,dimethylsulfoxide, tetrahydrofuran, dioxane, teributanol, toluene,N-methylpyrrolidone, water, alcohol or mixtures thereof in the presenceof a base such as e.g. lithium or sodium or potassium tertbutoxide,sodium or potassium or cesium carbonate, sodium or potassium hydroxide,tripotassium phosphate, triethylamine, ethyldiisopropylamine, ordiazabicycloundecene at temperatures ranging from 0 to 180° C.,preferably at 40 to 140° C. R¹—OH may also be used as solvent and may bedeprotonated with e.g. sodium hydride or sodium to form the alkoxideprior the addition of compound XXVI. To enhance the nucleophilicity ofR¹—O-metal the addition of crown ethers such as e.g. 18-crown-6 may beuseful. The coupling of isolatable intermediate XXVI and R¹—OH may alsobe conducted in the presence of a transition metal salt or complex suchas e.g. derived from Pd or Cu (Ullmann or Ullmann-type reaction). HereZ⁵ preferentially stands for iodine or trifluoromethansulfonate. Thesame solvents, bases, additives, and temperatures described for theuncatalyzed reaction may be used for the catalyzed reaction except forthat the latter is preferably executed under an inert gas atmospheresuch as argon or nitrogen. The catalyst is usually employed as elementas such or on charcoal, as a salt such as e.g. chloride, bromide,acetate, cyanide, or as a complex with ligands such as e.g. phosphites,phosphines, dibenzylideneacetone, 1,3-disubstituted imidazole ordihydroimidazole carbenes. If Z⁵ denotes arylboronic acid ortrifluoroborate R¹—OH may be attached via a copper(II) catalyzedreaction with a copper source such as e.g. copper(II) acetate in thepresence of a base such as e.g. triethylamine or pyridine in solventssuch as e.g. tetrahydrofuran, dichloromethane, 1,2-dichloroethane,acteonitrile, dioxane, dimethylformamide, dimethylacetamide, andN-methylpyrrolidone. The reaction may be carried out with stoichiometricamounts of copper catalyst or in the presence of a co-oxidant such ase.g. oxygen, pyridine-N-oxide, or tetramethylpiperidineoxide with onlycatalytic amounts of the catalyst. Dry solvents and the presence ofdrying agents such as e.g. molecular sieves are advantageous (see e.g.Angew. Chem. 2003, 115, pp. 5558-5607 and references quoted therein).

The Scheme 11 shows a preferred access to the aglycon V whichcorresponds to the Scheme 10 whereby the intermediate XXVI is preparedby Friedel-Crafts-acylation according to Scheme 5. The Scheme 11 and thefollowing sections describe preferred conditions and embodiments of theseventh aspect of this invention.

The assembly of aglycon V starts from the known benzoyl chloride XII andhalobenzene XXVII. The substituent X preferably denotes a bromine oriodine atom. A preferred meaning of the substituent Z⁵ is a fluorineatom. The first step, the preparation of benzophenone XXVI, can becharacterized as Friedel-Crafts or Friedel-Crafts-type acylation, awell-known method in organic synthesis. In principal, the benzoylchloride XII may be replaced by other benzoic acid derivatives such ase.g. benzoyl anhydrides, esters, or benzonitriles. This reaction isadvantageously carried out in the presence of a catalyst such as e.g.AlCl₃, FeCl₃, iodine, iron, ZnCl₂, sulfuric acid, ortrifluoromethanesulfonic acid, all of which are used in catalytic or upto stoichiometric amounts. A preferred catalyst is AlCl₃. The reactionmay be performed with or without additional solvents. Preferredadditional solvents are chlorinated hydrocarbons such as e.g.dichloromethane or 1,2-dichloroethane, hydrocarbons such as e.g. hexaneor mixtures thereof. According to a preferred embodiment the reaction iscarried out using an excess of the halobenzene XXVII which additionallyserves as a solvent. Preferred temperatures during the reaction rangefrom −30 to 140° C., preferably from 30 to 85° C. After completion ofthe reaction the reaction mixture may be quenched with water. Preferablythe organic solvents are removed. The intermediate XXVI may be isolated,preferably by crystallization, for example from water.

The second reaction step in Scheme 11 which is the replacement of Z⁵ byO—R¹ is analogous to the second reaction step in Scheme 10 as describedhereinbefore. According to a preferred embodiment O—R¹ is attachedaccording to a nucleophilic substitution on an aromatic ring in whichR¹—OH or an anion thereof replaces Z⁵ in an addition/eliminationsequence. The reaction is advantageously conducted in a solvent such ase.g. dimethylformamide, dimethylacetamide, dimethylsulfoxide,tetrahydrofuran, dioxane, tertbutanol, toluene, heptane,N-methylpyrrolidone, water, alcohol or a mixture thereof. Preferredsolvents are selected from dimethylformamide, tetrahydrofuran anddimethylacetamide.

This reaction is preferably carried out in the presence of a base suchas alkali C₁₋₄-alkoxides, alkali carbonates, alkali hydroxides, alkaliphosphates, tri(C₁₋₃ alkyl)amines and other N-containing organic bases.Examples of preferred bases are lithium or sodium or potassiumtertbutoxide, sodium or potassium or cesium carbonate, sodium orpotassium hydroxide, tripotassium phosphate, triethylamine,ethyldiisopropylamine, sodium bis(trimethylsilyl)amide (NaHMDS),diazabicycloundecene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) ormixtures thereof. More preferred bases are selected from sodium orpotassium tertbutoxide, sodium or potassium hydroxide, cesium carbonate,a mixture of cesium carbonate and potassium carbonate, or mixturesthereof. The amount of the base is preferably in the range from 1 to 5mol base per mol of intermediate XXVI. In case the base is a carbonate,phosphate or mixtures thereof, the total amount of the base is morepreferably in the range from 2 to 4 mol base, most preferably about 3mol base per mol of intermediate XXVI.

The reaction is preferably carried out at temperatures ranging fromabout −20 to 60° C., more preferably from about −10 to 40° C., even morepreferably from about 0 to 30° C.

The intermediate VII may be isolated from the reaction mixture,preferably by crystallization, for example from a mixture of ethanol andwater.

The synthetic route according to Scheme 11 concludes with the reductionof benzophenone VII to furnish aglycon V. Suitable reducing agents forthis conversion are silanes, in particular tri(C₁₋₃-alkyl)silanes, suchas e.g. triethylsilane, dimethylethylsilane and triisopropylsilane,borohydrides such as e.g. NaBH₄, and aluminum hydrides such as e.g.LiAlH₄ in the presence of a Lewis acid such as for example BF₃*OEt₂,tris(pentafluorophenyl)borane, trifluoroacetic acid, hydrochloric acid,aluminum chloride, or InCl₃. A particularly preferred reducing agent isEt₃SiH in the presence of a Lewis acid such as for example BF₃*OEt₂.Another particularly preferred reducing agent is NaBH₄ in the presenceof a Lewis acid such as for example trifluoroacetic acid.

The amount of the reducing agent, in particular of Et₃SiH, is preferablyfrom about 1 to 5 mol, even more preferably from about 2 to 4 mol, mostpreferably about 3 mol per mol of benzophenone VII. The amount of theLewis acid, in particular of BF₃*OEt₂, is preferably from about 1 to 5mol, even more preferably from about 1 to 3 mol per mol of benzophenoneVII.

The reduction reaction is preferably carried out in a solvent such ashalogenated hydrocarbons, for example dichloromethane and1,2-dichloroethane, toluene, benzene, hexane, acetonitrile and mixturesthereof.

Preferably the reduction is performed at temperatures from about −30 to100° C., preferably from about −20 to 50° C., even more preferably fromabout −10 to 25° C.

The aglycon of the formula V may be isolated and purified or may be usedin the synthesis of the final product of the formula I without furtherpurification.

Starting from the aglycon of the formula V the product of the formula Imay be obtained using the methods as described hereinbefore, preferablyusing the methods depicted and described in Scheme 2a.

In the reactions described hereinbefore, any reactive group present suchas ethynyl, hydroxy, amino, alkylamino or imino groups may be protectedduring the reaction by conventional protecting groups which are cleavedagain after the reaction.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, acteyl, trityl, benzyl or tetrahydropyranyl group.

Protecting groups for an amino, alkylamino or imino group may be, forexample, a formyl, acteyl, trifluoroacteyl, ethoxycarbonyl,tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group.

Moreover, the compounds and intermediates obtained may be resolved intotheir enantiomers and/or diastereomers, as mentioned hereinbefore. Thus,for example, cis/trans mixtures may be resolved into their cis and transisomers, and compounds with at least one optically active carbon atommay be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved bychromatography into the cis and trans isomers thereof, the compounds andintermediates obtained which occur as racemates may be separated bymethods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds or intermediates with at least 2 asymmetriccarbon atoms may be resolved into their diastereomers on the basis oftheir physical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a(+)-or (−)-menthyloxycarbonyl.

Furthermore, the compounds and intermediates of the present inventionmay be converted into the salts thereof, particularly for pharmaceuticaluse into the physiologically acceptable salts with inorganic or organicacids. Acids which may be used for this purpose include for examplehydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonicacid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citricacid, tartaric acid or maleic acid.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature, for example, particularly the methodsdescribed in WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836 and WO2004/063209.

In the foregoing and following text, H atoms of hydroxyl groups are notexplicitly shown in every case in structural formulae. The Examples thatfollow are intended to illustrate the present invention withoutrestricting it. In case the pressure is indicated in the unit “Torr”,the corresponding values can be converted into SI units by using 1torr=133.322 Pa. The terms “room temperature” or “ambient temperature”denote a temperature of about 20° C.

-   Ac acteyl,-   Bu butyl,-   Et ethyl,-   EtOAc ethylacetate,-   i-Pr iso-propyl,-   Me methyl,-   MeOH methanol,-   MTBE methyl-teributylether,-   THF tetrahydrofuran.

EXPERIMENTAL PROCEDURES Example I

(5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone

38.3 ml oxalyl chloride and 0.8 ml of dimethylformamide are added to amixture of 100 g of 5-bromo-2-chloro-benzoic acid in 500 mLdichloromethane. The reaction mixture is stirred for 14 h, then filteredand separated from all volatile constituents in a rotary evaporator. Theresidue is dissolved in 150 ml dichloromethane, the resulting solutionis cooled to −5° C., and 46.5 g of anisole are added. Then 51.5 g ofaluminum trichloride are added batchwise so that the temperature doesnot exceed 5° C. The solution is stirred for another 1 h at 1 to 5° C.and then poured onto crushed ice. The organic phase is separated, andthe aqueous phase is extracted three times with dichloromethane. Thecombined organic phases are washed with aqueous 1 M hydrochloric acid,twice with 1 M sodium hydroxide solution, and with brine. The organicphase is dried, the solvent is removed in vacuo, and the residue isrecrystallized from ethanol.

Yield: 86.3 g (64% of theory)

Mass spectrum (ESI⁺): m/z=325/327/329 (Br+Cl) [M+H]⁺

The following compounds may be obtained analogously to Example I:

(1)(5-bromo-2-chloro-phenyl)-(4-(R)-tetrahydrofuran-3-yloxy-phenyl)-methanone

The reaction is carried out according to the procedure described aboveexcept for 2 equivalents of aluminum trichloride are used. The reactionmixture is stirred at room temperature after the addition of aluminumtrichloride.

Mass spectrum (ESI⁺): m/z=382/384/386 (Br+Cl) [M+H]⁺

(2)(5-bromo-2-chloro-phenyl)-(4-(S)-tetrahydrofuran-3-yloxy-phenyl)-methanone

The reaction is carried out according to the procedure described aboveexcept for 2 equivalents of aluminum trichloride are used. The reactionmixture is stirred at room temperature after the addition of aluminumtrichloride.

Example II

(5-bromo-2-chloro-phenyl)-(4-fluoro-phenyl)-methanone

Variant A:

8.7 mL oxalyl chloride and 0.3 mL of dimethylformamide are added to amixture of 24 g of 5-bromo-2-chloro-benzoic acid in 150 mLdichloromethane. The reaction mixture is stirred for 14 h, then filteredand separated from all volatile constituents in a rotary evaporator. Theresidue is dissolved in 105 mL fluorobenzene and heated to 85° C. Then13.3 g of aluminum trichloride are added batchwise and the resultantmixture is stirred for 16 h at 85° C. After cooling to ambienttemperature, the reaction mixture is poured onto a mixture of 300 gcrushed ice and 100 mL concentrated hydrochloric acid. The resultantmixture is extracted two times with ethyl acetate. The combined organicextracts are washed with aqueous 1 M sodium hydroxide solution, aqueous1 M hydrochloric acid and brine. After drying over magnesium sulfate thesolvent is removed in vacuo. The solidified residue is washed withpetrol ether and dried in vacuo.

Yield: 25.0 g (80% of theory)

Mass spectrum (ESI⁺): m/z=313/315/317 (Br+Cl) [M+H]⁺

Variant B:

To a solution of 9.42 g 5-bromo-2-chloro-benzoic acid in 40 mL offluorobenzene and 0.1 mL of N,N-dimethylformamide is added 4 mL ofoxalyl chloride at 0 to 10° C. The solution is stirred at about 20° C.for 2 hours. The excess amount of oxalyl chloride is evaporated. Theresidue is diluted in 38 mL of fluorobenzene and 5.87 g of aluminumchloride is added at 0° C. in five portions. The solution is stirred at80° C. for 5 hours and quenched with 60 mL of water at 0 to 25° C. Theproduct is extracted in 50 mL of isopropylacetate and washed with twotimes of 40 mL 3 weight-% brine. The solvent is removed upon evaporationand the product is crystallized from heptane and water.

Yield: 11.94 g (92.4% of theory)

Mass spectrum (ESI⁺): m/z=314/316 (Cl) [M+H]⁺

Example III

(2-Chloro-5-iodo-phenyl)-(4-fluoro-phenyl)-methanone

To a solution of 48.94 g 2-chloro-5-iodo-benzoic acid in 180 mL offluorobenzene and 0.3 mL of N,N-dimethylformamide is added 16.2 mL ofoxalyl chloride at 0 to 10° C. The solution is stirred at about 20° C.for 2 hours. The excess amount of oxalyl chloride is evaporated. Theresidue is diluted in 166 mL of fluorobenzene and 25.93 g of aluminumchloride is added at 0 QC in five portions. The solution is stirred at75° C. for 1.5 hours and quenched with 300 mL of water at 0 to 25° C.The product is extracted in 300 mL of isopropylacetate and washed withtwo times of 200 mL brine (3 weight-%). The residue water and solvent isremoved upon evaporation.

Yield: 60.56 g (95% of theory)

Mass spectrum (ESI⁺): m/z=361/363 (Cl)[M+H]⁺

Example IV

(5-bromo-2-chloro-phenyl)-(4-(S)-tetrahydrofuran-3-yloxy-phenyl)-methanone

Variant A:

To a solution of 8.1 g (S)-3-hydroxy-tetrahydrofuran in 200 mldimethylformamide are added 10.3 g potassium tert-butoxide. The mixtureis stirred at room temperature for 10 min and then 24.0 g(5-bromo-2-chloro-phenyl)-(4-fluoro-phenyl)-methanone are added so withcooling in a water bath that the solution temperature remained below 35°C. The reaction mixture is stirred for 14 h at room temperature and thendiluted with 1000 mL water. The resultant mixture is extracted withethyl acetate and the combined extracts are washed with water and brine.After drying over magnesium sulfate the solvent is removed and theresidue is recrystallized from ethanol.

Yield: 22.5 g (77% of theory)

Mass spectrum (ESI⁺): m/z=382/384/386 (Br+Cl) [M+H]⁺

Variant B:

To a solution of 19.00 g(5-bromo-2-chloro-phenyl)-(4-fluoro-phenyl)-methanone in 60 mL oftetrahydrofuran and 5.87 g of (S)-3-hydroxytetrahydrofuran is added 9.60g of potassium tert-butoxide in 90 mL of tetrahydrofuran at 0 to 5° C.The solution is stirred at 10° C. for 0.5 hour. The reaction is quenchedwith 60 mL of water and 40 mL of methyl tert-butyl ether at 0 to 25° C.The product is washed with 80 mL of brine (3 weight-%). The solvent isremoved upon evaporation and crystallized in 135 mL of 2:1isopropylacetate/water.

Yield: 20.1 g (87% of theory)

Mass spectrum (ESI⁺): m/z=382/384 (Cl) [M+H]⁺

Example V

(2-Chloro-5-iodo-phenyl)-{4-[(S)-(tetrahydrofuran-3-yl)oxy]-phenyl}-methanone

To a solution of 60.56 g(2-chloro-5-iodo-phenyl)-(4-fluoro-phenyl)-methanone in 170 mL oftetrahydrofuran and 16.46 g of (S)-3-hydroxytetrahydrofuran is added 26g of potassium tert-butoxide in 250 mL of tetrahydrofuran at 0 to 5° C.The solution is stirred at 10° C. for 0.5 hour. The reaction is quenchedwith 170 mL of water and 170 mL of methyl tert-butyl ether at 0 to 25°C. The product is washed with 170 mL of brine (3 weight-%). The solventis removed upon evaporation and crystallized in 220 mL ofiso-propylacetate.

Yield: 65.1 g (90% of theory)

Mass spectrum (ESI⁺): m/z=428/430 (Cl) [M+H]⁺

Example VI

4-bromo-2-bromomethyl-1-chloro-benzene

4.0 g N-bromosuccinimide are slowly added to a solution of 5.0 g of4-bromo-1-chloro-2-hydroxymethyl-benzene and 5.9 g triphenylphosphine in50 mL of tetrahydrofuran chilled to 5° C. After 1 h stirring at ambienttemperature the precipitate is filtered off, and the solvent iseliminated in vacuo. The residue is purified by chromatography on silicagel (cyclohexane/ethyl acetate 50:1).

Yield: 4.9 g (76% of theory)

Mass spectrum (EI): m/z=282/284/286 (Br+Cl) [M]⁺

Example VII

4-bromo-1-chloro-2-(4-methoxy-benzyl)-benzene

A solution of 86.2 g(5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone and 101.5 mLtriethylsilane in 75 mL dichloromethane and 150 mL acetonitrile iscooled to 10° C. 50.8 mL of boron trifluoride etherate are added so thatthe temperature does not exceed 20° C. The solution is stirred for 14 hat ambient temperature, before another 9 mL triethylsilane and 4.4 mLboron trifluoride etherate are added. The solution is stirred for afurther 3 h at 45 to 50° C. and then cooled to ambient temperature. Asolution of 28 g potassium hydroxide in 70 mL of water is added, and theresultant mixture is stirred for 2 h. Then the organic phase isseparated, and the aqueous phase is extracted three times withdiisopropylether. The combined organic phases are washed twice with 2 Mpotassium hydroxide solution and once with brine and then dried oversodium sulfate. After the solvent is removed, the residue is washed withethanol and dried at 60° C.

Yield: 50.0 g (61% of theory)

Mass spectrum (ESI⁺): m/z=310/312/314 (Br+Cl) [M+H]⁺

The following compounds may be obtained analogously to Example VII:

(1) 4-bromo-1-chloro-2-(4-cyclopentyloxy-benzyl)-benzene

(2) (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene

(3) (R)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene

(4) 4-bromo-1-chloro-2-(4-tetrahydropyran-4-yloxy-benzyl)-benzene

(5) 4-bromo-1-chloro-2-(4-cyclohexyloxy-benzyl)-benzene

(6) 4-bromo-1-chloro-2-(4-cyclobutyloxy-benzyl)-benzene

Example VIII

4-(5-bromo-2-chloro-benzyl)-phenol

A solution of 14.8 g 4-bromo-1-chloro-2-(4-methoxy-benzyl)-benzene in150 ml dichloromethane is cooled in the ice bath. Then 50 ml of a 1 Msolution of boron tribromide in dichloromethane are added, and thesolution is stirred for 2 h at ambient temperature. The solution is thencooled in the ice bath again, and saturated potassium carbonate solutionis added dropwise. At ambient temperature the mixture is adjusted withaqueous 1 M hydrochloric acid to a pH of about 1, the organic phase isseparated off and the aqueous phase is extracted another three timeswith ethyl acetate. The combined organic phases are dried over sodiumsulphate, and the solvent is removed completely.

Yield: 13.9 g (98% of theory)

Mass spectrum (ESI⁻): m/z=295/297/299 (Br+Cl) [M−H]⁻

Example IX

4-Bromo-1-chloro-2-(4-cyclopentyloxy-benzyl)-benzene

To a mixture of 40.0 g 4-(5-bromo-2-chloro-benzyl)-phenol and 71.0 gcesium carbonate in 300 mL ethanol are added 23 mL iodocyclopentane. Themixture is stirred at 60° C. over night and then cooled to ambienttemperature. The ethanol is evaporated, and water is added to theresidue. The resulting mixture is extracted with ethyl acetate, thecombined extracts are dried over sodium sulfate, and the solvent isremoved. The residue is filtered through silica gel (cyclohexane/ethylacetate 100:1->10:1).

Yield: 34.4 g (70% of theory)

Mass spectrum (ESI⁺): m/z=364/366/368 (Br+Cl) [M]⁺

The following compounds may be obtained analogously to Example IX:

(1) (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=366/368/370 (Br+Cl) [M+H]⁺

(2) (R)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=366/368/370 (Br+Cl) [M]⁺

(3) 4-bromo-1-chloro-2-(4-tetrahydropyran-4-yloxy-benzyl)-benzene

(4) 4-bromo-1-chloro-2-(4-cyclohexyloxy-benzyl)-benzene

(5) 4-bromo-1-chloro-2-(4-cyclobutyloxy-benzyl)-benzene

Example X

(S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene

Variant A:

To a suspension of 250 g(5-bromo-2-chloro-phenyl)-{4-[(S)-(tetrahydro-furan-3-yl)oxy]-phenyl}-methanonein 1.33 L of acetonitrile and 314 mL of triethylsilane is added 93 mL ofboron trifluoride diethyl etherate at 20° C. The solution is stirred at20° C. for 16 hours. The mixture is filtered and the filtrate isquenched with 1.5 L of 1.5 M sodium hydroxide solution at 0 to 20° C.The solvent is removed upon evaporation and the residue is diluted with1.3 L of methyl tert-butyl ether. The product is washed with 1.2 L of0.1 M NaOH followed by 1 L of water. The solvent is removed uponevaporation and most of the triethylsilanol is removed upon thedistillation of toluene.

Yield: 218 g (90% of theory)

Mass spectrum (ESI⁺): m/z=368/370 (Cl) [M+H]⁺

Variant B:

To a suspension of 50.00 g(5-bromo-2-chloro-phenyl)-{4-[(S)-(tetrahydro-furan-3-yl)oxy]-phenyl}-methanonein 260 mL of acetonitrile and 34.68 g of dimethylethylsilane is added20.45 g of boron trifluoride diethyl etherate at 20° C. The solution isstirred at 20° C. for 16 hours. The mixture is filtered and the filtrateis quenched with 290 mL of 1.5 M sodium hydroxide solution at 0 to 20°C. The solvent is removed upon evaporation and the residue is dilutedwith 260 mL of methyl tert-butyl ether. The product is washed with 240mL of 0.1 M NaOH followed by 200 mL of water. The solvent is removedupon evaporation and most of the dimethylethylsilanol is removed uponthe distillation of heptane.

Yield: 45.76 g (95% of theory)

Mass spectrum (ESI⁺): m/z=368/370 (Cl) [M+H]⁺

Variant C:

To a suspension of 1.91 g(5-bromo-2-chloro-phenyl)-{4-[(S)-(tetrahydro-furan-3-yl)oxy]-phenyl}-methanoneand 0.38 g of sodium borohydride in 10 mL of methylene chloride (orfluorobenzene alternatively) is added 5.92 g of trifluoroacetic acid at0° C. The solution is stirred at 20° C. for 16 hours and quenched with20 mL of water and 20 mL of MTBE at 0 to 20° C. The product is washedwith 20 mL of water. The solvent is removed upon evaporation.

Yield: 1.6 to 1.75 g (87 to 95% of theory)

Variant D:

To a suspension of 1.91 g(5-bromo-2-chloro-phenyl)-{4-[(S)-(tetrahydro-furan-3-yl)oxy]-phenyl}-methanoneand 0.8 g of sodium borohydride in 10 mL of isopropyl acetate is added11.4 g of trifluoroacetic acid at 0° C. The solution is stirred at 20°C. for 16 hours and quenched with 20 mL of water and 20 mL of MTBE at 0to 20° C. The product is washed with 20 mL of water. The solvent isremoved upon evaporation.

Yield: 1.6˜1.75 g (87˜95% of theory)

Variant E:

To a solution of 0.19 g(5-bromo-2-chloro-phenyl)-{4-[(S)-(tetrahydro-furan-3-yl)oxy]phenyl}-methanonein 5 mL of tetrahydrofuran is added 0.04 g of sodium borohydride at 20°C. The solution is stirred at 20° C. for 16 hours and the solvent isexchanged to 5 mL of methylene chloride. To the slurry is added 0.35 mLof 1 M boron trichloride methylene chloride solution, 0.02 mL of waterand 0.24 mL of trifluoroacetic acid at 0° C., respectively. The mixtureis stirred at ambient temperature for 4 hours and quenched with 10 mL ofwater and 10 mL of MTBE at 0 to 20° C. The product is washed with 10 mLof water. The solvent is removed upon evaporation.

Yield: 0.18 g (97% of theory)

Example XI

(S)-4-iodo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene

Variant A:

To a suspension of 63.12 g(2-chloro-5-iodo-phenyl)-{4-[(S)-(tetrahydro-furan-3-yl)oxy]-phenyl}-methanonein 300 mL of acetonitrile and 40.14 g of dimethylethylsilane is added23.66 g of boron trifluoride diethyl etherate at 10° C. The solution isstirred at 20° C. for 16 hours. The reaction is quenched with 350 mL of1.5 M sodium hydroxide solution at 0 to 20° C. The product is diluted in200 mL of ethyl acetate. The product is washed with 200 mL of water. Thesolvent is removed upon evaporation and crystallized in 1:2acetonitrile/water.

Yield: 54.9 g (90% of theory)

Mass spectrum (ESI⁺): m/z=414/416 (Cl)[M+H]⁺

Variant B:

To a solution of 0.22 g(2-chloro-5-iodo-phenyl)-{4-[(S)-(tetrahydro-furan-3-yl)oxy]phenyl}-methanonein 5 mL of tetrahydrofuran is added 0.04 g of sodium borohydride at 20°C. The solution is stirred at 20° C. for 16 hours and the solvent isexchanged to 5 mL of methylene chloride. To the slurry is added 0.35 mLof 1 M boron trichloride methylene chloride solution, 0.02 mL of waterand 0.24 mL of trifluoroacetic acid at 0° C., respectively. The mixtureis stirred at 20° C. for 4 hours and quenched with 10 mL of water and 10mL of MTBE at 0 to 20° C. The product is washed with 10 mL of water. Thesolvent is removed upon evaporation and crystallized in 1:2acetonitrile/water.

Yield: 0.18 g (86% of theory)

Mass spectrum (ESI⁺): m/z=414/416 (Cl)[M+H]⁺

Example XII

2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone

A solution of 20 g D-glucono-1,5-lactone and 98.5 ml N-methylmorpholinein 200 ml of tetrahydrofuran is cooled to −5° C. Then 85 mltrimethylsilylchloride are added dropwise so that the temperature doesnot exceed 5° C. The solution is then stirred for 1 h at ambienttemperature, 5 h at 35° C. and again for 14 h at ambient temperature.After the addition of 300 ml of toluene the solution is cooled in an icebath, and 500 ml of water are added so that the temperature does notexceed 10° C. The organic phase is then separated and washed withaqueous sodium dihydrogen phosphate solution, water, and brine. Thesolvent is removed in vacuo, the residue is taken up in 250 ml oftoluene, and the solvent is again removed completely.

Yield: 52.5 g (approx. 90% pure)

Mass spectrum (ESI⁺): m/z=467 [M+H]⁺

Example XIII

1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(R)-tetrahydrofuran-3-yloxy-benzyl)-benzene

A solution of 5.40 g(R)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene in 85mL dry diethylether is cooled to −78° C. under argon. 18.5 mL of a 1.7 Msolution of tert-butyllithium in pentane are slowly added dropwise tothe cooled solution, and then the solution is stirred for 45 min at −78°C. Then a −78° C.—cold solution of 7.50 g (ca. 90% pure) of2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 35 mLdiethylether is added through a transfer needle. The resulting solutionis stirred for 2 h at −78° C., and then a solution of 2.5 mlmethanesulfonic acid in 65 mL of methanol is added. The cooling bath isremoved, and the solution is stirred for 16 h at ambient temperature.The solution is then neutralized with solid sodium hydrogencarbonate,most of the solvent is removed, and aqueous sodium hydrogen carbonatesolution is added to the residue. The resulting mixture is extractedwith ethyl acetate, the combined extracts are dried over sodium sulfate,and the solvent is removed to furnish the crude product that issubmitted to reduction without further purification.

Yield: 6.95 g (crude product)

Mass spectrum (ESI⁺): m/z=503/505 (Cl) [M+Na]⁺

The following compounds may be obtained analogously to Example XIII:

(1)1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene

(2)1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-cyclopentyloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=501/503 (Cl) [M+Na]⁺

Example XIV

1-Chloro-4-(2,3,4,6-tetra-O-acteyl-D-glucopyranos-1-yl)-2-(4-(R)-tetrahydrofuran-3-yloxy-benzyl)-benzene

A solution of 6.95 g1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(R)-tetrahydro-furanyloxy-benzyl)-benzeneand 4.7 mL triethylsilane in 40 ml dichloromethane and 80 mlacetonitrile is cooled to −10° C. Then 1.25 mL boron trifluorideetherate are added dropwise so that the solution temperature remainedbelow 0° C. The solution is stirred for 3 h in an ice bath. Aqueoussodium hydrogen carbonate solution is added, and the resulting mixtureis extracted with ethyl acetate. The organic phase is dried over sodiumsulfate, the solvent is removed, and the residue is taken up in 80 mLdichloromethane. Then 8.5 mL of pyridine, 7.8 mL of acetic anhydride and100 mg of 4-dimethylaminopyridine are added. The solution is stirred for1 h at ambient temperature and then diluted with water. The mixture isextracted with dichloromethane, the organic phase is washed with 1 Mhydrochloric acid and dried over sodium sulfate. After the solvent isremoved the residue is recrystallized from ethanol to furnish theproduct as white crystals.

Yield: 2.20 g (25% of theory)

Mass spectrum (ESI⁺): m/z=619/621 (Cl) [M+H]⁺

The following compounds may be obtained analogously to Example XIV:

(1)1-Chloro-4-(2,3,4,6-tetra-O-acteyl-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene

(2)1-Chloro-4-(2,3,4,6-tetra-O-acteyl-D-glucopyranos-1-yl)-2-(4-cyclopentyloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=640/642 (Cl) [M+Na]⁺

Example XV

1-Chloro-4-(2,3,4,6-tetra-O-benzyl-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene

A solution of 0.37 g1-chloro-4-(1-methoxy-2,3,4,6-tetra-O-benzyl-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzeneand 0.21 mL triethylsilane in 2.5 ml dichloromethane and 7.5 mlacetonitrile is cooled to −20° C. Then 0.13 mL boron trifluorideetherate are added dropwise over 1 min. The resulting mixture is allowedto warm to −10° C. over 1 h. Aqueous sodium hydrogen carbonate solutionis added, and the resulting mixture is extracted with ethyl acetate. Theorganic phase is washed with brine, dried over sodium sulfate, andconcentrated under vacuum. The resulting residue was purified by columnchromatography to give a mixture of alpha and beta isomers (alpha: betaratio approximately 1:3) as a thick oil in quantitative yield.

Yield: 0.36 g (100% of theory)

Mass spectrum (ESI⁺): m/z=833/835 (Cl) [M+Na]⁺

Example XVI

1-Chloro-4-(2,3,4,6-tetra-O-allyl-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene

A solution of 0.37 g1-chloro-4-(1-methoxy-2,3,4,6-tetra-O-allyl-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuranyloxy-benzyl)-benzeneand 0.28 mL triethylsilane in 2.5 ml dichloromethane and 7.5 mlacetonitrile is cooled to −20° C. Then 0.16 mL boron trifluorideetherate are added dropwise over 1 min. The resulting mixture is allowedto warm to −10° C. over 1 h. Aqueous sodium hydrogen carbonate solutionis added, and the resulting mixture is extracted with ethyl acetate. Theorganic phase is washed with brine, dried over sodium sulfate, andconcentrated under vacuum. The resulting residue was purified by columnchromatography to give a mixture of alpha and beta isomers (alpha: betaratio approximately 1:9) as a thick oil.

Yield: 0.30 g (85% of theory)

Mass spectrum (ESI⁺): m/z=633/635 (Cl) [M+Na]⁺

Example XVII

1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-(R)-tetrahydrofuran-3-yloxy-benzyl)-benzene

To a solution of 2.201-chloro-4-(2,3,4,6-tetra-O-acteyl-D-glucopyranos-1-yl)-2-(4-(R)-tetrahydrofuran-3-yloxy-benzyl)-benzenein 30 mL of methanol is added 4 mL of 4 M aqueous potassium hydroxidesolution. The solution is stirred at ambient temperature for 1 h andthen neutralized with 4 M hydrochloric acid. The methanol is evaporated,and the residue is diluted with brine and extracted with ethyl acetate.The combined organic extracts are dried over sodium sulfate, and thesolvent is removed. The residue is chromatographed on silica gel(dichloromethane/methanol 1:0->4:1).

Yield: 1.45 g (90% of theory)

Mass spectrum (ESI⁺): m/z=451/453 (Cl) [M+H]⁺

The following compounds may be obtained analogously to Example XVII:

(1)1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=451/453 (Cl) [M+H]⁺

(2)1-Chluoro-4-(β-D-glucopyranos-1-yl)-2-(4-cyclopentyloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=466/468 (Cl) [M+NH₄]⁺

(3)1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-tetrahydropyran-4-yloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=487/489 (Cl) [M+Na]⁺

(4)1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-cyclohexyloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=480/482 (Cl) [M+NH₄]⁺

(5)1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-cyclobutyloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=452/454 (Cl) [M+NH₄]⁺

Example XVIII

1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene

Variant A:

Step i)

To a solution of 5.5 mL 2.0 M BuMgCl in THF in 30 mL of tetrahydrofuranis added 12 mL of 2.5 M BuLi in hexane at −15 to −5° C. and stirred at−10° C. for 20 minutes. 10.00 g of(S)-3-[4-(5-bromo-2-chloro-benzyl)-phenoxy]-tetrahydrofuran in 10 mL ofTHF is added at −23 to −20° C. and stirred at −22° C. for 20 min. 20.32g of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 7 mL of THFis added at −20 to −18° C. The reaction is then stirred at −20° C. for 1hour and warmed to −12° C. in another hour. 60 mL of 25 weight-% aqueousNH₄Cl solution is added to quench the reaction. 40 mL of MTBE is addedand the organic layer is separated. The aqueous layer is extracted with30 mL of EtOAc. The combined organic phases are dried over MgSO₄ andconcentrated.

Step ii)

The residue of step i) is dissolved in 100 mL of MeOH and 0.52 g ofMeSO₃H and stirred at 43° C. for 4 hours. The reaction is then cooled to5° C. and quenched with 20 mL of 10 weight-% NaHCO₃ aqueous solution.MeOH is distilled under reduced pressure and 25 mL of water and 25 mL ofEtOAc are added. The organic layer is separated, and the aqueous phaseis extracted with 20 mL of EtOAc. The combined organic phases are driedand concentrated to dryness.

Step iii)

The residue of step ii) was dissolved in 63 mL of MeCN and 43 mL ofCH₂Cl₂ and cooled to −20° C. 7.59 g of triethylsilane is added, followedby addition of 6.95 g of boron trifluoride etherate. The reaction iswarmed up gradually from −20 to 10° C. over 2 h. 40 g of 10 weight-%NaHCO₃ is added to quench the reaction. The organic solvents are removedunder reduced pressure. 50 mL of isopropyl acetate and 12 mL of waterare charged and the mixture is stirred at ambient temperature forovernight. The product is filtered and dried.

Yield: 13.5 g (55% of theory)

Mass spectrum (ESI⁺): m/z=451/453 (Cl) [M+H]⁺

Variant B:

Instead of BuMgCl in step i) of variant A i-PrMgCl is used. The stepsii) and iii) are as in variant A.

Variant C:

Instead of BuMgCl in step i) of variant A i-PrMgCl/LiCl is used. Thesteps ii) and iii) are as in variant A.

Variant D:

Step i)

To a solution of 2.90 g(S)-3-[4-(5-bromo-2-chloro-benzyl)-phenoxy]-tetrahydrofuran in 4 mL ofTHF at 0 to 20° C. (or alternatively at 20° C.), is slowly charged 8.4mL of 1.0 M PrMgCl/LiCl in THF. The reaction is stirred at 20° C. for 16hours and cooled to −23° C. 4.3 g of2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 2 mL of THF isadded dropwise. The reaction is then stirred at −20° C. for 2 h. AqueousNH₄Cl solution (25 weight-%, 12 mL) is added to quench the reaction.MTBE (8 mL) is added and the organic layer is separated. The aqueouslayer is extracted with EtOAc (30 mL). The combined organic phases aredried over MgSO₄ and concentrated.

Step ii)

The residue of step i) is dissolved in MeOH (20 mL) and MeSO₃H (260 mg,2.8 mmol) and stirred at 43° C. for 3 h. The reaction is then cooled to5° C. and quenched with 10 weight-% NaHCO₃ aqueous solution (12 mL).MeOH is distilled under reduced pressure and water (4 mL) and EtOAc (30mL) are added. The organic layer is separated, and the aqueous phase isextracted with EtOAc (20 ml). The combined organic phases are dried andconcentrated to dryness.

Step iii)

The residue of step ii) is dissolved in MeCN (17 mL) and CH₂Cl₂ (11 mL)and cooled to −20° C. Triethylsilane (2.08 g, 17.9 mmol) is added,followed by addition of boron trifluoride etherate (1.9 g, 13.4 mmol).The reaction is warmed up gradually from −20 to 10° C. over 2 h. 10%NaHCO₃ (25 mL) is added to quench the reaction. Organic solvents areremoved under reduced pressure. Isopropyl acetate (15 mL) and water (5ml) are charged and the mixture is stirred at ambient temperature forovernight. The product is filtered and dried.

Yield: 0.91 g (27% of theory)

Mass spectrum (ESI⁺): m/z=451/453 (Cl) [M+H]⁺

Variant E:

Step i)

To a solution of 2.90 g(S)-3-[4-(5-iodo-2-chloro-benzyl)-phenoxy]-tetrahydrofuran in 4 mL ofTHF at −23° C., is slowly charged 8.4 mL of 1.0 M i-PrMgCl/LiCl in THF.The reaction is stirred at −22° C. for 20 minutes. 4.3 g of2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 2 mL of THF isadded dropwise. The reaction is then stirred at −20° C. for 2 h. AqueousNH₄Cl solution (25 weight-%, 12 mL) is added to quench the reaction.MTBE (8 mL) is added and the organic layer is separated. The aqueouslayer is extracted with EtOAc (30 mL). The combined organic phases aredried over MgSO₄ and concentrated.

Step ii)

The residue of step i) is dissolved in MeOH (20 mL) and MeSO₃H (260 mg,2.8 mmol) and stirred at 43° C. for 3 h. The reaction is then cooled to5° C. and quenched with 10 weight-% NaHCO₃ aqueous solution (12 mL).MeOH is distilled under reduced pressure and water (4 mL) and EtOAc (30mL) are added. The organic layer is separated, and the aqueous phase isextracted with EtOAc (20 ml). The combined organic phases are dried andconcentrated to dryness.

Step iii)

The residue of step ii) is dissolved in MeCN (17 mL) and CH₂Cl₂ (11 mL)and cooled to −20° C. Triethylsilane (2.08 g, 17.9 mmol) is added,followed by addition of boron trifluoride etherate (1.9 g, 13.4 mmol).The reaction is warmed up gradually from −20 to 10° C. over 2 h. 25 mlaqueous 10 weight-% NaHCO₃ are added to quench the reaction. Organicsolvents are removed under reduced pressure. Isopropyl acetate (15 mL)and water (5 ml) are charged and the mixture is stirred at ambienttemperature for overnight. The product is filtered and dried.

Yield: 2.2 g (65% of theory)

Mass spectrum (ESI⁺): m/z=451/453 (Cl)[M+H]⁺

The invention claimed is:
 1. Process for preparing the compounds ofgeneral formula II,

wherein R¹ denotes R-tetrahydrofuran-3-yl or S-tetrahydrofuran-3-yl; andR² independently of one another denote hydrogen, (C₁₋₁₈-alkyl)carbonyl,(C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl, aryl-(C₁₋₃-alkyl)-carbonyl,aryl- C₁₋₃-alkyl -alkyl, allyl, R^(a)R^(b)R^(c)Si, or CR^(a)R^(b)OR^(c),wherein two adjacent groups R² may be linked with each other to form abridging group SiR^(a)R^(b), CR^(a)R^(b) or CR^(a)OR^(b)—CR^(a)OR^(b);R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl, arylor aryl-C₁₋₃-alkyl, while the alkyl groups may be mono- orpolysubstituted by halogen; L1 independently of one another are selectedfrom among fluorine, chlorine, bromine, C₁₋₃-alkyl , C₁₋₄-alkoxy andnitro; while by the aryl groups mentioned in the definition of the abovegroups are meant phenyl or naphthyl groups, which may be mono-orpolysubstituted with L1; said method comprised of the steps of reactinga glucose derivative of the formula XXXV

wherein R² is defined as hereinbefore and Hal denotes F, Cl, Br,C₁₋₃-alkylcarbonyloxy, C₁₋₃-alkyloxycarbonyloxy or C₁₋₃-alkyloxy; with ametallated aglycon of the formula VI

wherein R¹ is defined as hereinbefore and M denotes a zinc moiety; toyield the product of the formula II.
 2. The process according to claim1, wherein R² independently of one another denote C₁₋₄-alkylcarbonyl,C₁₋₄-alkyloxycarbonyl, arylmethyl or R^(a)R^(b)R^(c)Si.